Benzotriazoles and methods of prophylaxis or treatment of metabolic-related disorders thereof

ABSTRACT

The present invention relates to certain benzotriazole carboxylic acid or ester derivatives of Formula (I), pharmaceutically acceptable salts and solvates thereof, which exhibit useful pharmaceutical properties, for example, as agonists for the GPCR referred to as hRUP38. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the prophylaxis or treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of -glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers and the like.

FIELD OF THE INVENTION

The present invention relates to certain benzotriazole carboxylic acidderivatives, and pharmaceutically acceptable salts thereof, whichexhibit useful pharmaceutical properties, for example as agonists forthe receptor referred herein as hRUP38. The receptor hRUP38 has beenidentified to be highly homologous to the receptor hRUP25. The ligandfor hRUP25 is nicotinic acid (i.e., niacin). Despite the extremely highhomology between these two receptors, a series of receptor specificagonists for the hRUP38 has been identified belonging to the generalclass of compounds known as benzotriazole carboxylic acids derivatives.

BACKGROUND OF THE INVENTION

Antilipolytic Agents

Atherosclerosis and stroke are the numbers one and number three leadingcauses of death of both men and women in the United States. Type 2diabetes is a public health problem that is serious, widespread andincreasing. Elevated levels of low density lipoprotein (LDL) cholesterolor low levels of high density lipoprotein (HDL) cholesterol are,independently, risk factors for atherosclerosis and associatedcardiovascular pathologies. In addition, high levels of plasma freefatty acids are associated with insulin resistance and type 2 diabetes.One strategy for decreasing LDL-cholesterol, increasing HDL-cholesterol,and decreasing plasma free fatty acids is to inhibit lipolysis inadipose tissue. This approach involves regulation of hormone sensitivelipase, which is the rate-limiting enzyme in lipolysis. Lipolytic agentsincrease cellular levels of cAMP, which leads to activation of hormonesensitive lipase within adipocytes. Agents that lower intracellular cAMPlevels, by contrast, would be antilipolytic.

It is also worth noting in passing that an increase in cellular levelsof cAMP down-regulates the secretion of adiponectin from adipocytes[Delporte, M L et al. Biochem J (2002) July; the disclosure of which isincorporated by reference in its entirety]. Reduced levels of plasmaadiponectin have been associated with metabolic-related disorders,including atherosclerosis, coronary heart disease, insulin resistanceand type 2 diabetes [Matsuda, M et al. J Biol Chem (2002) July andreviewed therein; the disclosure of which is incorporated by referencein its entirety].

Compounds of the invention inhibit the production and release of freefatty acids from adipose tissue, likely via an inhibition of adenylylcyclase, a decrease in intracellular cAMP levels, and a concomitantdecrease in hormone sensitive lipase activity. Agonists thatdown-regulate hormone sensitive lipase activity leading to a decrease inplasma free fatty acid levels are likely to have therapeutic value. Theconsequence of decreasing plasma free fatty acids is two-fold. First, itwill ultimately lower LDL-cholesterol and raise HDL-cholesterol levels,independent risk factors, thereby reducing the risk of mortality due tocardiovascular incidence subsequent to atheroma formation. Second, itwill provide an increase in insulin sensitivity in individuals withinsulin resistance or type 2 diabetes.

Agonists of antilipolytic GPCRs having limited tissue distributionbeyond adipose may be especially valuable in view of the diminishedopportunity for potentially undesirable side-effects.

This application is related to U.S. Provisional Patent Application Ser.No. 60/423,819 that is incorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses benzotriazole carboxylicacid and ester derivatives as shown in Formula (I):

wherein:

R₁ is C₁₋₈ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, wherein the C₁₋₈alkyl, C₃₋₆ cycloalkyl and C₁₋₆ haloalkyl groups are optionallysubstituted with 1, 2, 3 or 4 substituents selected from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino,aryl, substituted aryl, C₁₋₆ dialkylamino, carbo C₁alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl, heterocyclyl,hydroxyl, nitro or thiol;

R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and

R₅ is H or C₁₋₆ alkyl; or

-   -   a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, when R₅ is ethyl, and R₂, R₃ and R₄ are H then R₁is not methyl or triphenylmethyl.

In some embodiments, when R₅ is n-pentyl, and R₂, R₃ and R₄ are H thenR₁ is not n-butyl.

In some embodiments, when R₅ is methyl, and R₂, R₃ and R₄ are H then R₁is not pyrrolidin-1-ylmethyl, 3-tert-butyl-2-hydroxy-5-methyl-benzyl,methyl, or dimethylaminomethyl.

In some embodiments, when R₅ is methyl, R₂ is carbomethoxy (i.e.—CO₂CH₃), and R₃ and R₄ are both H then R₁ is not methyl.

In some embodiments, when R₂, R₃, R₄ and R₅ are all H then R₁ is not2-amino-2-carboxy-ethyl, pyrrolidin-1-ylmethyl, isopropyl, methyl,benzyl, n-butyl, or carboxymethyl (i.e., —CH₂CO₂H).

In some embodiments, when R₂, R₄, and R₅ are all H and R₃ is methoxythen R₁ is not methyl.

One aspect of the present invention encompasses benzotriazole carboxylicacid and ester derivatives as shown in Formula (I) wherein:

R₁ is C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, where the C₃₋₆ cycloalkyl orC₁₋₆ haloalkyl group is optionally substituted with C₁₋₆acyl, C₁₋₆acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido,C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio,C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆alkoxy, carboxy, cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol;

R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and

R₅ is H or C₁₋₆ alkyl; or

a pharmaceutically acceptable salt, solvate or hydrate thereof.

Another aspect of the present invention encompasses compounds of thegroup consisting of 1-Cyclopentyl-1H-benzotriazole-5-carboxylic acid;1-(2′-Butyl)-1H-benzotriazole-5-carboxylic acid;1-(3′-Pentyl)-1H-benzotriazole-5-carboxylic acid;1-Cyclohexyl-1H-benzotriazole-5-carboxylic acid;1-Propyl-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-1H-benzotriazole-5-carboxylic acid;1-(3′-Isopropoxy-propyl)-1H-benzotriazole-5-carboxylic acid;1-(Tetrahydro-furan-2′-ylmethyl)-H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-1H-benzotriazole-5-carboxylic acid;1-(2-Methoxy-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(3′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid;1-(4′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid;1-[2′-(4″-Methoxy-phenyl)-ethylamino]-1H-benzotriazole-5-carboxylicacid;1-[2′-(3″-Methoxy-phenyl)-ethylamino]-1H-benzotriazole-5-carboxylicacid; 1-(3′,5′-Difluorobenzyl)-1H-benzotriazole-5-carboxylic acid;1-(2-Ethylsulfanyl-ethyl)-1H-benzotriazole-5-carboxylic acid;1-t-Butyl-1H-benzotriazole-5-carboxylic acid;1-(3′-Hydroxy-propyl)-1H-benzotriazole-5-carboxylic acid;1-(1′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid;1-(3′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid;1-Heptyl-1H-benzotriazole-5-carboxylic acid;1-(2′-Methoxy-1′-methyl-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Hydroxy-1′-hydroxymethyl-ethyl)-1H-benzotriazole-5-carboxylicacid; 1-Ethyl-1H-benzotriazole-5-carboxylic acid;1-Pentyl-1H-benzotriazole-5-carboxylic acid;1-(2′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Ethoxy-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(1′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid;1-Benzhydryl-1H-benzotriazole-5-carboxylic acid;1-Allyl-1H-benzotriazole-5-carboxylic acid;1-Butyl-1H-benzotriazole-5-carboxylic acid;1-(Cyclopropylmethyl)-1H-benzotriazole-5-carboxylic acid;1-(But-2-ynyl)-1H-benzotriazole-5-carboxylic acid;1-(4′-Methyl-pentyl)-1H-benzotriazole-5-carboxylic acid; and1-(3′-Methyl-butyl)-1H-benzotriazole-5-carboxylic acid; or apharmaceutically acceptable salt or a solvate thereof.

Another aspect of the present invention encompasses certainpharmaceutical compositions comprising a compound of Formula (I) orsubgenera thereof in combination with a pharmaceutically acceptablecarrier.

Another aspect of the present invention encompasses pharmaceuticalcompositions, as described herein, further comprising one or more agentselected from the group consisting of α-glucosidase inhibitor, aldosereductase inhibitor, biguanide, HMG-CoA reductase inhibitor, squalenesynthesis inhibitor, fibrate, LDL catabolism enhancer, angiotensinconverting enzyme inhibitor, insulin secretion enhancer andthiazolidinedione.

Another aspect of the present invention encompasses methods ofmodulating a RUP38 receptor comprising contacting the receptor with atherapeutically effective amount of a compound as described herein. Insome embodiments, the compound is an agonist of the receptor.

Another aspect of the present invention encompasses methods ofmodulating a RUP38 receptor in an individual comprising contacting thereceptor with a therapeutically effective amount of a compound asdescribed herein. In some embodiments, the modulation treats ametabolic-related disorder.

Another aspect of the present invention encompasses methods ofmodulating RUP38 receptor function in a cell, tissue or individualcomprising contacting the cell, tissue or individual with atherapeutically effective amount of a compound as described herein. Insome embodiments, the RUP38 receptor function is associated with ametabolic-related disorder.

Another aspect of the present invention encompasses methods of treatmentof a metabolic-related disorder comprising administering to anindividual in need of such treatment a therapeutically effective amountof a compound or a pharmaceutical composition as described herein.

In some embodiments of the present invention, the metabolic-relateddisorder is selected from the group consisting of dyslipidemia,atherosclerosis, coronary heart disease, insulin resistance, obesity,impaired glucose tolerance, atheromatous disease, hypertension, stroke,Syndrome X, heart disease and type 2 diabetes. In some embodiments, themetabolic-related disorder is selected from the group consisting ofdyslipidemia, atherosclerosis, coronary heart disease, insulinresistance and type 2 diabetes.

In some embodiments of the present invention, the individual is amammal. In some embodiments, the mammal is a human.

Another aspect of the present invention encompasses methods of producinga pharmaceutical composition comprising admixing a compound as describedherein and a pharmaceutically acceptable carrier.

Another aspect of the present invention is a compound according to anyof the embodiments described herein or a pharmaceutical composition asdescribed herein for use in a method of treatment of the human or animalbody by therapy.

Another aspect of the present invention is a compound according to anyof the embodiments described herein or a pharmaceutical composition asdescribed herein for use in a method of treatment of a metabolic-relateddisorder of the human or animal body by therapy.

Another aspect of the present invention encompasses the use of compoundsof Formula (I) for the manufacture of a medicament for use in thetreatment of a metabolic-related disorder.

Another aspect of the present invention encompasses the use of compoundsof Formula (I) for the manufacture of a medicament for use in thetreatment of a metabolic-related disorder selected from the groupconsisting of dyslipidemia, atherosclerosis, coronary heart disease,insulin resistance, obesity, impaired glucose tolerance, atheromatousdisease, hypertension, stroke, Syndrome X, heart disease and type 2diabetes.

Another aspect of the present invention encompasses the use of compoundsof Formula (I) for the manufacture of a medicament for use in thetreatment of atherosclerosis.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. FIG. 1 presents screening data via adenylyl cyclase assay forhRUP38. Note that nicotinic acid does not activate inhibition offorskolin stimulated cAMP in hRUP38-expressing CHO cells whereas1-Isopropyl-1H-benzotriazole-5-carboxylic acid does.1-Isopropyl-1H-benzotriazole-5-carboxylic acid has no effect on CHOcells expressing hRUP25. The EC₅₀ for1-Isopropyl-1H-benzotriazole-5-carboxylic acid is 166 nM.

FIG. 2. Nicotinic acid and 1-Isopropyl-1H-benzotriazole-5-carboxylicacid were separately dose-dependently applied to isoproterenolstimulated (100 nM) primary human adipocytes. FIG. 2 illustrates theability of 1-Isopropyl-1H-benzotriazole-5-carboxylic acid to inhibitisoproterenol stimulated lipolysis in adipocyte primary cultures derivedfrom human subcutaneous fat in a dose-dependant manner comparable tothat of nicotinic acid.

DETAILED DESCRIPTION

One aspect of the present invention encompasses benzotriazole carboxylicacid and ester derivatives as shown in Formula (I):

wherein:

R₁ is C₁₋₈ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, wherein the C₁₋₈alkyl, C₃₋₆ cycloalkyl and C₁₋₆ haloalkyl groups are optionallysubstituted with 1, 2, 3 or 4 substituents selected from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino,aryl, substituted aryl, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl, heterocyclyl,hydroxyl, nitro or thiol;

R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and

R₅ is H or C₁₋₆ alkyl; or

-   -   a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, when R₅ is ethyl, and R₂, R₃ and R₄ are H then R₁is not methyl or triphenylmethyl.

In some embodiments, when R₅ is n-pentyl, and R₂, R₃ and R₄ are H thenR₁ is not n-butyl.

In some embodiments, when R₅ is methyl, and R₂, R₃ and R₄ are H then R₁is not pyrrolidin-1-ylmethyl, 3-tert-butyl-2-hydroxy-5-methyl-benzyl,methyl, or dimethylaminomethyl. The group pyrrolidin-1-ylmethyl can berepresented by the following formula:

In some embodiments, when R₅ is methyl, R₂ is carbomethoxy (i.e.—CO₂CH₃), and R₃ and R₄ are both H then R₁ is not methyl.

In some embodiments, when R₂, R₃, R₄ and R₅ are all H then R₁ is not2-amino-2-carboxy-ethyl, pyrrolidin-1-ylmethyl, isopropyl, methyl,benzyl, n-butyl, or carboxymethyl (i.e., —CH₂CO₂H). The group2-amino-2-carboxy-ethyl can be represented by the following formula:

In some embodiments, when R₂, R₄, and R₅ are all H and R₃ is methoxythen R₁ is not methyl.

One aspect of the present invention encompasses benzotriazole carboxylicacid and ester derivatives as shown in Formula (I) wherein:

R₁ is C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, where the C₃₋₆ cycloalkyl orC₁₋₆ haloalkyl group is optionally substituted with C₁₋₆acyl, C₁₋₆acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamido,C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio,C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆alkoxy, carboxy, cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol;

R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and

R₅ is H or C₁₋₆ alkyl; or

a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of the presentinvention. In some embodiments, compounds of the present invention areR. In some embodiments, compounds of the present are S. In someembodiments, compounds of the present invention are racemic mixtures.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

In some embodiments, the invention is a compound where R₅ is C₁₋₆alkyl.

In some embodiments, the invention is a compound where R₅ is H and isrepresented by Formula (Ia) shown below:

In some embodiments, R₂, R₃ and R₄ are each independently H or halogen.In some embodiments, R₂, R₃ and R₄ are each independently H or F.

In some embodiments, the invention is a compound where R₁ is C₁₋₈ alkyloptionally substituted with substituents selected from the groupconsisting of C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₂₋₆ alkynyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, aryl, substitutedaryl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkylsulfinyl,C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl, heterocyclyl,and hydroxyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group. In some embodiments, R₁ is selected from the groupconsisting of 2-butyl, 3-pentyl, 1-propyl, t-butyl, 1-butyl,4-Methyl-pentyl, 3-methyl-butyl, 1,3-dimethyl-butyl, 3,3-dimethyl-butyl,1-heptyl, ethyl, and 1-pentyl, and 1,2-dimethyl-propyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a substituted aryl group. Insome embodiments, R₁ is selected from the group consisting of3-methoxy-benzyl, 4-methoxy-benzyl, 4-methoxy-phenyl ethyl,3-methoxy-phenyl ethyl, 3,5-difluorobenzyl, and benzhydryl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a C₁₋₆ alkoxy group. In someembodiments, R₁ is selected from the group consisting of3-isopropoxypropyl, 2-methoxy-ethyl, 2-methoxy-1-methyl-ethyl, and2-ethoxy-ethyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a heterocyclyl group. In someembodiments, R₁ is tetrahydro-furan-2-ylmethyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a C₁₋₆ alkylthio group. In someembodiments, R₁ is 2-ethylsulfanyl-ethyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a hydroxyl group. In someembodiments, R₁ is 3-hydroxy-propyl, 2-hydroxy-1-hydroxymethyl-ethyl, or2-hydroxy-1-hydroxymethyl-ethyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a C₂₋₆ alkenyl group. In someembodiments, R₁ is allyl (i.e., —CH₂CH═CH₂).

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a C₃₋₆ cycloalkyl group. In someembodiments, R₁ is cyclopropylmethyl.

In some embodiments, the invention is a compound where R₁ is a C₁₋₈alkyl group optionally substituted with a C₂₋₆ alkynyl group. In someembodiments, R₁ is but-2-ynyl.

In some embodiments, the invention is a compound where R₁ is C₃₋₆cycloalkyl optionally substituted with C₁₋₃ alkoxy, C₁₋₃ alkyl, C₁₋₃alkylureyl, amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino,carbo-C₁₋₃-alkoxy, carboxy, cyano, halogen, C₁₋₃ haloalkoxy, C₁₋₃haloalkyl, hydroxyl, nitro or thiol. Illustrated examples for when R₁ isC₃₋₆ cycloalkyl include cyclopropyl, Formula (Ib); cyclobutyl, Formula(Ic); cyclopentyl, Formula (Id); cyclohexyl, Formula (Ie) and the like.

In some embodiments, R₁ is C₃₋₅ cycloalkyl optionally substituted withC₁₋₃ alkyl, halogen, C₁₋₃ haloalkyl or hydroxyl. In some embodiments, R₁is C₃₋₅ cycloalkyl optionally substituted with C₁₋₃ alkyl or halogen. Insome embodiments, R₁ is C₃₋₄ cycloalkyl optionally substituted with 1 to4 fluorine atoms. In some embodiments, R₁ is a cyclopropyl or cyclobutylgroup.

In some embodiments, the invention is a compound where R₁ is C₁₋₆haloalkyl optionally substituted with C₁₋₃ alkoxy, C₁₋₃ alkylureyl,amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy,cyano, halogen, C₁₋₃ haloalkoxy, hydroxyl, nitro or thiol. In someembodiments, R₁ is C₁₋₅ haloalkyl optionally substituted with amino,C₁₋₃ alkoxy or hydroxyl. In some embodiments, R₁ is CF₃, CF₃CH₂,CF₃CF₂CH₂, (CF₃)₂CH, CF₃CF₂CF₂CH₂ or (CF₃)₂CHCH₂. In some embodiments,R₁ is a 2,2,2-trifluoroethyl, Formula (If); or2,2,2-trifluoro-1-trifluoromethyl-ethyl group, Formula (Ig).

In some embodiments, the invention is a compound where R₂, R₃ and R₄ areindependently H, C₁₋₃ alkoxy, C₁₋₃ alkyl, amino, C₁₋₃ alkylamino, C₁₋₄dialkylamino, halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl, hydroxyl, nitroor thiol. In some embodiments, R₂, R₃ and R₄ are independently H, C₁₋₃alkyl, amino, halogen, C₁₋₃ haloalkyl or hydroxyl. In some embodiments,R₂, R₃ and R₄ are independently H, methyl, ethyl, amino, fluorine,chlorine, trifluoromethyl, or hydroxyl.

In some embodiments, the invention is a compound where R₁ is cyclopropylor cyclobutyl; and R₂, R₃ and R₄ are independently H, methyl, ethyl,amino, fluorine, chlorine, trifluoromethyl, or hydroxyl. In someembodiments, R₂, R₃ and R₄ are independently H, methyl, fluorine,chlorine or trifluoromethyl.

In some embodiments, the invention encompasses a compound wherein R₁ iscyclopropyl and R₅ is H and has the following chemical name.Substitutions are based on the numbering system as shown in Formula(Ih):

1-Cyclopropyl-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-7-fluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-6-fluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-4-fluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-6,7-difluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-4,7-difluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-4,6-difluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-4,6,7-trifluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-7-chloro-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-6-chloro-1H-benzotriazole-5-carboxylic acid; or1-Cyclopropyl-4-chloro-1H-benzotriazole-5-carboxylic acid; or apharmaceutically acceptable salt as described herein below or a solvateas described herein below. Alternatively, a specific compound of theinvention as described herein above and below wherein R₅═H the compoundmay alternatively be an ester where R₅ is C₁₋₆ alkyl. In one embodimentof the present invention, R₅ is C₁₋₄ alkyl, in one embodiment R₅ is C₁₋₂alkyl, in one embodiment R₅ is C₂₋₆ alkyl, in one embodiment R₅ is C₃₋₆alkyl, and in one embodiment R₅ is C₄₋₆ alkyl.

In some embodiments, the invention encompasses a compound wherein R₁ iscyclobutyl and R₅ is H and has the following chemical name.Substitutions are based on the numbering system as shown in Formula(Ii):

1-Cyclobutyl-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-7-fluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-6-fluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-4-fluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-6,7-difluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-4,7-difluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-4,6-difluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-4,6,7-trifluoro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-7-chloro-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-6-chloro-1H-benzotriazole-5-carboxylic acid; or1-Cyclobutyl-4-chloro-1H-benzotriazole-5-carboxylic acid; or apharmaceutically acceptable salt, solvate or ester thereof.

In some embodiments, the invention encompasses a compound wherein R₁ is2,2,2-trifluoro-ethyl and R₅ is H and has the following chemical name.Substitutions are based on the numbering system as shown in Formula(Ij):

1-(2,2,2-Trifluoro-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(2,2,2-Trifluoro-ethyl)-7-fluoro-1H-benzotriazole-5-carboxylic acid;1-(2,2,2-Trifluoro-ethyl)-6-fluoro-1H-benzotriazole-5-carboxylic acid;1-(2,2,2-Trifluoro-ethyl)-6-fluoro-1H-benzotriazole-5-carboxylic acid;1-(2,2,2-Trifluoro-ethyl)-6,7-difluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-ethyl)-4,7-difluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-ethyl)-4,6-difluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-ethyl)-4,6,7-trifluoro-1H-benzotriazole-5-carboxylicacid; 1-(2,2,2-Trifluoro-ethyl)-7-chloro-1H-benzotriazole-5-carboxylicacid; 1-(2,2,2-Trifluoro-ethyl)-6-chloro-1H-benzotriazole-5-carboxylicacid; or1-(2,2,2-Trifluoro-ethyl)-4-chloro-1H-benzotriazole-5-carboxylic acid;or a pharmaceutically acceptable salt, solvate or ester thereof.

In some embodiments, the invention encompasses a compound wherein R₁ is2,2,2-trifluoro-ethyl and R₅ is H and has the following chemical name.Substitutions are based on the numbering system as shown in Formula(Ik):

1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-7-fluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-6-fluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)₄-fluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-6,7-difluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-4,7-difluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-4,6-difluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-4,6,7-trifluoro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-7-chloro-1H-benzotriazole-5-carboxylicacid;1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-6-chloro-1H-benzotriazole-5-carboxylicacid; or1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)₄-chloro-1H-benzotriazole-5-carboxylicacid; or a pharmaceutically acceptable salt, solvate or ester thereof.

One aspect of the present invention encompasses a pharmaceuticalcomposition according to any one of the compound embodiments of Formula(I) in combination with a pharmaceutically acceptable carrier.

One aspect of the present invention encompasses a pharmaceuticalcomposition comprising a compound of Formula (I):

wherein:

-   -   R₁ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, wherein        each C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl group is        optionally substituted with C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆        alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆        alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio,        C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino,        carbo C₁₋₆ alkoxy, carboxy, cyano, C₃₋₆ cycloalkyl, C₁₋₆        dialkylcarboxamido, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆        haloalkylthio, hydroxyl, nitro or thiol;    -   R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy,        C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido,        C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₁₋₆        dialkylamino, carbo C₁₋₆ alkoxy, carboxy, cyano, C₃₋₆        cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆ haloalkoxy,        C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl,        C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and    -   R₅ is H or C₁₋₆ alkyl; or    -   a pharmaceutically acceptable salt, solvate or hydrate thereof        in combination with a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is where R₁ is C₁₋₆alkyl optionally substituted with C₁₋₃ alkoxy, C₁₋₃ alkylureyl, amino,C₁₋₃ alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy, cyano,C₃₋₅ cycloalkyl, halogen, C₁₋₃ haloalkoxy, hydroxyl, nitro or thiol. Insome embodiments, R₁ is C₁₋₆ alkyl optionally substituted with C₁₋₃alkoxy, amino, C₃₋₅ cycloalkyl or hydroxyl. In some embodiments, R₁ isC₁₋₆ alkyl further substituted with C₃₋₅ cycloalkyl. In someembodiments, R₁ is cyclopropylmethyl as shown by Formula (Im),dicyclopropylmethyl as shown by Formula (In), 1-(1-cyclopropyl-ethyl) asshown by Formula (Io), 1-(2-cyclopropyl-ethyl) as shown in Formula (Ip),cyclobutylmethyl as shown by Formula (Iq), 1-(1-cyclobutyl-ethyl) asshown by Formula (Ir) or 1-(2-cyclobutyl-ethyl) as shown by Formula(Is).

In some embodiments, the pharmaceutical composition is where R₁ is C₁₋₆alkyl. In some embodiments, R₁ is CH₃, CH₃CH₂, CH₃CH₂CH₂, (CH₃)₂CH,CH₃CH₂CH₂CH₂, (CH₃)₂CHCH₂, CH₃CH₂CH(CH₃), (CH₃)₃C, CH₃CH₂CH₂CH₂CH₂,(CH₃)₂CHCH₂CH₂, CH₃CH₂CH(CH₃)CH₂, CH₃CH₂CH₂CH(CH₃), (CH₃)₃CCH₂,CH₃CH₂C(CH₃)₂ or CH₃CHCH₃CHCH₃. In some embodiments, R₁ is CH₃, CH₃CH₂,CH₃CH₂CH₂, (CH₃)₂CH, CH₃CH₂CH₂CH₂, (CH₃)₂CHCH₂, CH₃CH₂CH(CH₃), or(CH₃)₃C.

In some embodiments, the pharmaceutical composition is where R₁ is C₁₋₆haloalkyl optionally substituted with C₁₋₃ alkoxy, C₁₋₃ alkylureyl,amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy,cyano, C₁₋₃ haloalkoxy, hydroxyl, nitro or thiol. In some embodiments,R₁ is C₁₋₅ is haloalkyl optionally substituted with amino, C₁₋₃ alkoxyor hydroxyl. In some embodiments, R₁ is CF₃, CF₃CH₂, CF₃CF₂CH₂,(CF₃)₂CH, CF₃CF₂CF₂CH₂ or (CF₃)₂CHCH₂.

In some embodiments, the pharmaceutical composition is where R₂, R₃ andR₄ are independently H, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylthio, amino,cyano, C₃₋₅ cycloalkyl, halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl,hydroxyl, nitro or thiol. In some embodiments, R₂, R₃ and R₄ areindependently H, C₁₋₂ alkoxy, C₁₋₂ alkyl, C₁₋₂ alkylthio, amino, cyano,C₃₋₅ cycloalkyl, halogen, C₁₋₂ haloalkoxy, C₁₋₂ haloalkyl, hydroxyl,nitro or thiol. In some embodiments, R₂, R₃ and R₄ are independently H,methoxy, methyl, methylsulfide, amino, cyano, cyclopropyl, cyclobutyl,fluorine atom, chlorine atom, bromine atom, trifluoromethoxy,difluoromethoxy, fluoromethoxy, trifluoromethyl, difluoromethyl,hydroxyl, or thiol. In some embodiments, R₂, R₃ and R₄ are independentlyH, methoxy, methyl, methylsulfide, amino, cyano, fluorine atom, chlorineatom, trifluoromethoxy, difluoromethoxy, trifluoromethyl,difluoromethyl, or hydroxyl.

In some embodiments, the pharmaceutical composition is where R₁ is C₃₋₆cycloalkyl optionally substituted with C₁₋₃ alkoxy, C₁₋₃ alkyl, C₁₋₃alkylureyl, amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino,carbo-C₁₋₃-alkoxy, carboxy, cyano, halogen, C₁₋₃ haloalkoxy, C₁₋₃haloalkyl, hydroxyl, nitro or thiol. In some embodiments, R₁ is C₃₋₅cycloalkyl optionally substituted with C₁₋₃ alkyl, halogen, C₁₋₃haloalkyl or hydroxyl. In some embodiments, R₁ is C₃₋₅ cycloalkyloptionally substituted with C₁₋₃ alkyl or halogen. In some embodiments,R₁ is C₃₋₄ cycloalkyl optionally substituted with 1 to 7 fluorine atoms.In some embodiments, R₁ is a cyclopropyl or cyclobutyl group.

In some embodiments, the pharmaceutical composition is where R₁ is C₁₋₆alkyl; and R₂, R₃ and R₄ are independently H, C₁₋₃ alkoxy, C₁₋₃ alkyl,C₁₋₃ alkylureyl, amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino,carbo-C₁₋₃-alkoxy, carboxy, cyano, halogen, C₁₋₃ haloalkoxy, C₁₋₃haloalkyl, hydroxyl, nitro or thiol. In some embodiments, R₁ is C₁₋₄alkyl; and R₂, R₃ and R₄ are independently H, C₁₋₃ alkyl, amino,halogen, C₁₋₃ haloalkyl or hydroxyl. In some embodiments, R₂, R₃ and R₄are independently H, methyl, ethyl, amino, fluorine, chlorine,trifluoromethyl, or hydroxyl. In some embodiments, R₂, R₃ and R₄ areindependently H, methyl, amino, fluorine, trifluoromethyl or hydroxyl.

In some embodiments, the pharmaceutical composition is where R₁ is C₃₋₆cycloalkyl; and R₂, R₃ and R₄ are independently H, C₁₋₃ alkoxy, C₁₋₃alkyl, C₁₋₃ alkylureyl, amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino,carbo-C₁₋₃-alkoxy, carboxy, cyano, halogen, C₁₋₃ haloalkoxy, C₁₋₃haloalkyl, hydroxyl, nitro or thiol. In some embodiments, R₁ is C₃₋₄cycloalkyl; and R₂, R₃ and R₄ are independently H, C₁₋₃ alkyl, amino,halogen, C₁₋₃ haloalkyl or hydroxyl. In some embodiments, R₂, R₃ and R₄are independently H, methyl, ethyl, amino, fluorine, chlorine,trifluoromethyl, or hydroxyl. In some embodiments, R₂, R₃ and R₄ areindependently H, methyl, amino, fluorine, trifluoromethyl or hydroxyl.

In some embodiments, the pharmaceutical composition is where R₁ is C₁₋₆haloalkyl; and R₂, R₃ and R₄ are independently H, C₁₋₃ alkoxy, C₁₋₃alkyl, C₁₋₃ alkylureyl, amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino,carbo-C₁₋₃-alkoxy, carboxy, cyano, halogen, C₁₋₃ haloalkoxy, C₁₋₃haloalkyl, hydroxyl, nitro or thiol. In some embodiments, R₁ is C₁₋₃haloalkyl; and R₂, R₃ and R₄ are independently H, C₁₋₃ alkyl, amino,halogen, C₁₋₃ haloalkyl or hydroxyl. In some embodiments, R₂, R₃ and R₄are independently H, methyl, ethyl, amino, fluorine, chlorine,trifluoromethyl, or hydroxyl. In some embodiments, R₂, R₃ and R₄ areindependently H, methyl, amino, fluorine, trifluoromethyl or hydroxyl.

In one aspect of the present invention, the pharmaceutical compositionfurther comprising one or more agents selected from the group consistingof α-glucosidase inhibitor, aldose reductase inhibitor, biguanide,HMG-CoA reductase inhibitor, squalene synthesis inhibitor, fibrate, LDLcatabolism enhancer, angiotensin converting enzyme inhibitor, insulinsecretion enhancer and thiazolidinedione.

In some embodiments of the invention the pharmaceutical compositionfurther comprises a α-glucosidase inhibitor. In some embodiments, theα-glucosidase inhibitor is acarbose, voglibose or miglitol. In someembodiments, the α-glucosidase inhibitor is voglibose.

In some embodiments of the invention the pharmaceutical compositionfurther comprises an aldose reductase inhibitor. In some embodiments,the aldose reductase inhibitor is tolurestat; epalrestat; imirestat;zenarestat; zopolrestat; or sorbinil.

In some embodiments of the invention the pharmaceutical compositionfurther comprises a biguanide. In some embodiments, the biguanide isphenformin, metformin or buformin. In some embodiments, the biguanide ismetformin.

In some embodiments of the invention the pharmaceutical compositionfurther comprises a HMG-CoA reductase inhibitor. In some embodiments,the HMG-CoA reductase inhibitor is rosuvastatin, pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.

In some embodiments of the invention the pharmaceutical compositionfurther comprises a fibrate. In some embodiments, the fibrate isbezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate,clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil,nicofibrate, pirifibrate, ronifibrate, simfibrate, or theofibrate.

In some embodiments of the invention the pharmaceutical compositionfurther comprises an angiotensin converting enzyme inhibitor. In someembodiments, the angiotensin converting enzyme inhibitor is captopril,enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril ortrandolapril.

In some embodiments of the invention the pharmaceutical compositionfurther comprises an insulin secretion enhancer. In some embodiments,the insulin secretion enhancer is tolbutamide; chlorpropamide;tolazamirde; acetohexamide; glycopyramide; glibenclamide; gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; tolcyclamide, glimepiride,nateglinide, or mitiglinide.

In some embodiments of the invention the pharmaceutical compositionfurther comprises a thiazolidinedione. In some embodiments, thethiazolidinedione is rosiglitazone or pioglitazone. In some embodiments,the thiazolidinedione is rosiglitazone.

One aspect of the present invention encompasses a method of prophylaxisof a metabolic disorder comprising administering to a patient in need ofsuch administration a prophylactically effective amount of a compound ora pharmaceutical composition according to any of the embodimentsdisclosed herein. In some embodiments, the metabolic disorder isdyslipidemia, atherosclerosis, coronary heart disease, insulinresistance, obesity, impaired glucose tolerance, atheromatous disease,hypertension, stroke, Syndrome X, heart disease and type 2 diabetes. Insome embodiments, the metabolic disorder is dyslipidemia,atherosclerosis, coronary heart disease, insulin resistance and type 2diabetes.

In some embodiments, compounds of the invention have at least about 2times greater selectivity for hRUP38 compared to hRUP25 (i.e., EC₅₀hRUP25÷EC₅₀ hRUP38=about 2). In some embodiments, compounds of theinvention have at least about 4 times greater selectivity for hRUP38compared to hRUP25. In some embodiments, compounds of the invention haveabout 6 times greater selectivity for hRUP38 compared to hRUP25.

One aspect of the present invention encompasses a method of treatment ofa metabolic disorder comprising administrating to a patient in need ofsuch administration a therapeutically effective amount of a compound ora pharmaceutical composition according to any of the embodimentsdisclosed herein. In some embodiments, the metabolic disorder isdyslipidemia, atherosclerosis, coronary heart disease, insulinresistance, obesity, impaired glucose tolerance, atheromatous disease,hypertension, stroke, Syndrome X, heart disease and type 2 diabetes. Insome embodiments, the metabolic disorder is dyslipidemia,atherosclerosis, coronary heart disease, insulin resistance and type 2diabetes.

One aspect of the present invention encompasses the use of a compoundfor production of a medicament for use in prophylaxis or treatment of ametabolic disorder wherein the compound is of Formula (I):

wherein:

R₁ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, where the C₁₋₆alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl group is optionally substitutedwith C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino,C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy, cyano, C₃₋₆ cycloalkyl,C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,nitro or thiol;

R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and R₅is H or C₁₋₆ alkyl; or

a pharmaceutically acceptable salt, solvate or hydrate thereof

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament wherein R₁is C₁₋₆ alkyl optionally substituted with C₁₋₃ alkoxy, C₁₋₃ alkylureyl,amino, C₁₋₃ alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy,cyano, C₃₋₅ cycloalkyl, halogen, C₁₋₃ haloalkoxy, hydroxyl, nitro orthiol. In some embodiments, R₁ is C₁₋₆ alkyl optionally substituted withC₁₋₃ alkoxy, amino, C₃₋₅ cycloalkyl or hydroxyl. In some embodiments, R₁is C₁₋₆ alkyl further substituted with C₃₋₅ cycloalkyl. In someembodiments, R₁ is cyclopropylmethyl [Formula (Im)], dicyclopropylmethyl[Formula (In)], 1-(1-cyclopropyl-ethyl) [Formula (Io)],1-(2-cyclopropyl-ethyl) [Formula (Ip)], cyclobutylmethyl [Formula (Iq)],1-(1-cyclobutyl-ethyl) [Formula (Ir)] or 1-(2-cyclobutyl-ethyl) [Formula(Is].

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₁ is C₁₋₆ alkyl. In some embodiments,R₁ is CH₃, CH₃CH₂, CH₃CH₂CH₂, (CH₃)₂CH, CH₃CH₂CH₂CH₂, (CH₃)₂CHCH₂,CH₃CH₂CH(CH₃), (CH₃)₃C, CH₃CH₂CH₂CH₂CH₂, (CH₃)₂CHCH₂CH₂,CH₃CH₂CH(CH₃)CH₂, CH₃CH₂CH₂CH(CH₃), (CH₃)₃CCH₂, CH₃CH₂C(CH₃)₂ orCH₃CHCH₃CHCH₃. In some embodiments, R₁ is CH₃, CH₃CH₂, CH₃CH₂CH₂,(CH₃)₂CH, CH₃CH₂CH₂CH₂, (CH₃)₂CHCH₂, CH₃CH₂CH(CH₃), or (CH₃)₃C.

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₁ is C₁₋₆ haloalkyl optionallysubstituted with C₁₋₃ alkoxy, C₁₋₃ alkylureyl, amino, C₁₋₃ alkylamino,C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy, cyano, C₁₋₃ haloalkoxy,hydroxyl, nitro or thiol. In some embodiments, R₁ is C₁₋₅ haloalkyloptionally substituted with amino, C₁₋₃ alkoxy or hydroxyl. In someembodiments, R₁ is CF₃, CF₃CH₂ CF₃CF₂CH₂, (CF₃)₂CH, CF₃CF₂CF₂CH₂ or(CF₃)₂CHCH₂.

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₂, R₃ and R₄ are independently H; C₁₋₄alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylthio, amino, cyano, C₃₋₅ cycloalkyl,halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl, hydroxyl, nitro or thiol. Insome embodiments, R₂, R₃ and R₄ are independently H, C₁₋₂ alkoxy, C₁₋₂alkyl, C₁₋₂ alkylthio, amino, cyano, C₃₋₅ cycloalkyl, halogen, C₁₋₂haloalkoxy, C₁₋₂ haloalkyl, hydroxyl, nitro or thiol. In someembodiments, R₂, R₃ and R₄ are independently H, methoxy, methyl,methylsulfide, amino, cyano, cyclopropyl, cyclobutyl, fluorine atom,chlorine atom, bromine atom, trifluoromethoxy, difluoromethoxy,fluoromethoxy, trifluoromethyl, difluoromethyl, hydroxyl, or thiol. Insome embodiments, R₂, R₃ and R₄ are independently H, methoxy, methyl,methylsulfide, amino, cyano, fluorine atom, chlorine atom,trifluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, orhydroxyl.

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₁ is C₃₋₆ cycloalkyl optionallysubstituted with C₁₋₃ alkoxy, C₁₋₃ alkyl, C₁₋₃ alkylureyl, amino, C₁₋₃alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy, cyano,halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl, hydroxyl, nitro or thiol. Insome embodiments, R₁ is C₃₋₅ cycloalkyl optionally substituted with C₁₋₃alkyl, halogen, C₁₋₃ haloalkyl or hydroxyl. In some embodiments, R₁ isC₃₋₅ cycloalkyl optionally substituted with C₁₋₃ alkyl or halogen. Insome embodiments, R₁ is C₃₋₄ cycloalkyl optionally substituted with 1 to7 fluorine atoms. In some embodiments, R₁ is a cyclopropyl or cyclobutylgroup.

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₁ is C₁₋₆ alkyl; and R₂, R₃ and R₄ areindependently H, C₁₋₃ alkoxy, C₁₋₃ alkyl, C₁₋₃ alkylureyl, amino, C₁₋₃alkylamino, C₁₋₃ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy, cyano,halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl, hydroxyl, nitro or thiol. Insome embodiments, R₁ is C₁₋₄ alkyl; and R₂, R₃ and R₄ are independentlyH, C₁₋₃ alkyl, amino, halogen, C₁₋₃ haloalkyl or hydroxyl. In someembodiments, R₂, R₃ and R₄ are independently H, methyl, ethyl, amino,fluorine, chlorine, trifluoromethyl, or hydroxyl. In some embodiments,R₂, R₃ and R₄ are independently H, methyl, amino, fluorine,trifluoromethyl or hydroxyl.

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₁ is C₃₋₆ cycloalkyl; and R₂, R₃ and R₄are independently H, C₁₋₃ alkoxy, C₁₋₃ alkyl, C₁₋₃ alkylureyl, amino,C₁₋₃ alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy, cyano,halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl, hydroxyl, nitro or thiol. Insome embodiments, R₁ is C₃₋₄ cycloalkyl; and R₂, R₃ and R₄ areindependently H, C₁₋₃ alkyl, amino, halogen, C₁₋₃ haloalkyl or hydroxyl.In some embodiments, R₂, R₃ and R₄ are independently H, methyl, ethyl,amino, fluorine, chlorine, trifluoromethyl, or hydroxyl. In someembodiments, R₂, R₃ and R₄ are independently H, methyl, amino, fluorine,trifluoromethyl or hydroxyl.

Some embodiments of the present invention encompass the use of acompound disclosed herein where R₁ is C₁₋₆ haloalkyl; and R₂, R₃ and R₄are independently H, C₁₋₃ alkoxy, C₁₋₃ alkyl, C₁₋₃ alkylureyl, amino,C₁₋₃ alkylamino, C₁₋₄ dialkylamino, carbo-C₁₋₃-alkoxy, carboxy, cyano,halogen, C₁₋₃ haloalkoxy, C₁₋₃ haloalkyl, hydroxyl, nitro or thiol. Insome embodiments, R₁ is C₁₋₃ haloalkyl; and R₂, R₃ and R₄ areindependently H, C₁₋₃ alkyl, amino, halogen, C₁₋₃ haloalkyl or hydroxyl.In some embodiments, R₂, R₃ and R₄ are independently H, methyl, ethyl,amino, fluorine, chlorine, trifluoromethyl, or hydroxyl. In someembodiments, R₂, R₃ and R₄ are independently H, methyl, amino, fluorine,trifluoromethyl or hydroxyl.

One aspect of the invention encompasses the use according to embodimentsdisclosed herein further comprising one or more agents selected from thegroup consisting of a α-glucosidase inhibitor, aldose reductaseinhibitor, biguanide, HMG-CoA reductase inhibitor, squalene synthesisinhibitor, fibrate, LDL catabolism enhancer, angiotensin convertingenzyme inhibitor, insulin secretion enhancer and thiazolidinedione.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising a α-glucosidase inhibitor. In some embodiments, theα-glucosidase inhibitor is acarbose, voglibose or miglitol. In someembodiments, the α-glucosidase inhibitor is voglibose.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising an aldose reductase inhibitor. In some embodiments, thealdose reductase inhibitor is tolurestat; epalrestat; imirestat;zenarestat; zopolrestat; or sorbinil.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising a biguanide. In some embodiments, the biguanide isphenformin, metformin or buformin. In some embodiments, the biguanide ismetformin.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising a HMG-CoA reductase inhibitor. In some embodiments, theHMG-CoA reductase inhibitor is rosuvastatin, pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising a fibrate. In some embodiments, the fibrate is bezafibrate,beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, or theofibrate.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising an angiotensin converting enzyme inhibitor. In someembodiments, the angiotensin converting enzyme inhibitor is captopril,enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril ortrandolapril.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising an insulin secretion enhancer. In some embodiments, theinsulin secretion enhancer is tolbutamide; chlorpropamide; tolazamide;acetohexamide; glycopyramide; glibenclamide; gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; tolcyclamide, glimepiride,nateglinide, or mitiglinide.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament furthercomprising a thiazolidinedione. In some embodiments, thethiazolidinedione is rosiglitazone or pioglitazone. In some embodiments,the thiazolidinedione is rosiglitazone.

Some embodiments of the present invention encompass the use of acompound of the invention for the production of a medicament wherein themetabolic disorder is dyslipidemia, atherosclerosis, coronary heartdisease, insulin resistance, obesity, impaired glucose tolerance,atheromatous disease, hypertension, stroke, Syndrome X, heart diseaseand type 2 diabetes. In some embodiments, the metabolic disorder isdyslipidemia, atherosclerosis, coronary heart disease, insulinresistance and type 2 diabetes.

One aspect of the present invention encompasses a process for preparinga composition comprising admixing a compound and a pharmaceuticallyacceptable carrier wherein the compound is of Formula (I):

wherein:

R₁ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, where the C₁₋₆alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl group is optionally substitutedwith C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino,C₁₋₆ dialkylamino, carbo C₁₋₆alkoxy, carboxy, cyano, C₃₋₆ cycloalkyl,C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,nitro or thiol;

R₂, R₃ and R₄ are independently H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro or thiol; and

R₅ is H or C₁₋₆ alkyl; or

a pharmaceutically acceptable salt, solvate or hydrate thereof.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

Definitions

The scientific literature has adopted a number of terms, for consistencyand clarity, the following definitions will be used throughout thispatent document.

AGONISTS shall mean materials (e.g., ligands, candidate compounds) thatactivate an intracellular response when they bind to the receptor. Insome embodiments, AGONISTS are those materials not previously known toactivate the intracellular response when they bind to the receptor (e.g.to enhance GTPγS binding to membranes or to lower intracellular cAMPlevel). In some embodiments, AGONISTS are those materials not previouslyknown to inhibit lipolysis when they bind to the receptor.

AMINO ACID ABBREVIATIONS used herein are set out in TABLE 1: TABLE 1ALANINE ALA A ARGININE ARG R ASPARAGINE ASN N ASPARTIC ACID ASP DCYSTEINE CYS C GLUTAMIC ACID GLU E GLUTAMINE GLN Q GLYCINE GLY GHISTIDINE HIS H ISOLEUCINE ILE I LEUCINE LEU L LYSINE LYS K METHIONINEMET M PHENYLALANINE PHE F PROLINE PRO P SERINE SER S THREONINE THR TTRYPTOPHAN TRP W TYROSINE TYR Y VALINE VAL V

ANTAGONISTS shall mean materials (e.g., ligands, candidate compounds)that competitively bind to the receptor at the same site as the agonistsbut which do not activate an intracellular response, and can therebyinhibit the intracellular responses elicited by agonists. ANTAGONISTS donot diminish the baseline intracellular response in the absence of anagonist. In some embodiments, ANTAGONISTS are those materials notpreviously known to compete with an agonist to inhibit the cellularresponse when they bind to the receptor, e.g. wherein the cellularresponse is GTPγS binding to membranes or to the lowering ofintracellular cAMP level.

ATHEROSCLEROSIS is intended herein to encompass disorders of large andmedium-sized arteries that result in the progressive accumulation withinthe intima of smooth muscle cells and lipids.

CHEMICAL GROUP, MOIETY or RESIDUE shall have the following meaning inthe specification and Formulae described herein:

-   -   The term “C₁₋₆ acyl” denotes a C₁₋₆ alkyl radical attached to a        carbonyl group wherein the definition of alkyl has the same        definition as described herein; some examples include acetyl,        propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl,        heptanoyl, and the like.    -   The term “C₁₋₆ acyloxy” denotes an acyl radical attached to an        oxygen atom wherein acyl has the same definition has described        herein; some examples include acetyloxy, propionyloxy,        butanoyloxy, iso-butanoyloxy and the like.    -   The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6        carbons, some embodiments are 2 to 4 carbons, some embodiments        are 2 to 3 carbons, and some embodiments have 2 carbons. Both E        and Z isomers are embraced by the term “alkenyl.” Furthermore,        the term “alkenyl” includes di- and tri-alkenyls. Accordingly,        if more than one double bond is present then the bonds may be        all E or Z or a mixtures of E and Z. Examples of an alkenyl        include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,        3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,        5-hexanyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl,        6-heptenyl, 2,4-hexadienyl and the like.    -   The term “C₁₋₆ alkoxy” as used herein denotes a radical alkyl,        as defined herein, attached directly to an oxygen such as        methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,        iso-butoxy, sec-butoxy and the like.    -   The term “alkyl” denotes a radical containing 1 to 8 carbons,        some embodiments are 1 to 6 carbons, some embodiments are 1 to 4        carbons, some embodiments are 1 to 3 carbons, and some        embodiments are 1 or 2 carbons. Examples of an alkyl include        methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,        2-butyl, t-butyl, amyl, t-amyl, 1-pentyl, 2,2-dimethyl-propyl,        3-pentyl, 3-methyl-butyl, 1,3-dimethyl-butyl,        3,3-dimethyl-butyl, hexyl, 3-methyl-butyl, 4-methyl-pentyl,        1-heptyl, and the like.    -   The term “C₁₋₆ alkylcarboxamido” denotes a single alkyl group        attached to the amine of an amide, wherein alkyl has the same        definition as found herein. Examples include        N-methylcarboxamide, N-ethylcarboxamide,        N-(iso-propyl)carboxamide and the like.    -   The term “C₁₋₆ alkynyl” denotes a radical containing 2 to 6        carbons, some embodiments are 2 to 4 carbons, some embodiments        are 2 to 3 carbons, and some embodiments have 2 carbons.        Examples of an alkynyl include ethynyl, 1-propynyl, 2-propynyl,        1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,        3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,        4-hexynyl, 5-hexynyl and the like. The term “alkynyl” includes        di- and tri-ynes.    -   The term “C₁₋₆ alkylsulfinyl” denotes an alkyl radical attached        to a sulfoxide radical of the formula: —S(O)— wherein the alkyl        radical has the same definition as described herein. Examples        include methylsulfinyl, ethylsulfinyl and the like.    -   The term “C₁₋₆ alkylsulfonyl” denotes an alkyl radical attached        to a sulfone radical of the formula: —S(O)₂— wherein the alkyl        radical has the same definition as described herein. Examples        include methylsulfonyl, ethylsulfonyl and the like.    -   The term “C₁₋₆ alkylthio” denotes an alkyl radical attached to a        sulfide of the formula: —S— wherein the alkyl radical has the        same definition as described herein. Examples include        methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, isopropylsulfanyl        and the like.    -   The term “C₁₋₆ alkylureyl” denotes the group of the formula:        —NC(O)N— wherein one are both of the nitrogens are substituted        with the same or different alkyl group wherein alkyl has the        same definition as described herein. Examples of an alkylureyl        include, CH₃NHC(O)NH—, NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—,        (CH₃)₂N(O)NH—, (CH₃)₂N(O)NCH₃—, CH₃CH₂NHC(O)NH—,        CH₃CH₂NHC(O)NCH₃—, and the like.    -   The term “amino” denotes the group —NH₂.    -   The term “C₁₋₆ alkylamino” denotes an alkyl radical attached to        an amino radical wherein the alkyl radical has the same meaning        as described herein.    -   The term “C₁₋₆ dialkylamino” denotes an amino substituted with        two of the same or different alkyl radicals wherein alkyl        radical has the same definition as described herein. A C₁        dialkylamino may be represented by the following groups:    -    Examples of C₁₋₆ dialkylamino include, but not limited to,        dimethylamino, methylethylamino, diethylamino,        methylpropylamino, methylisopropylamino, and the like. Some        examples include dimethylamino, methylethylamino, diethylamino        and the like.    -   The term “aryl” denotes an aromatic ring radical containing 6 to        10 ring carbons, for example phenyl, napthyl and the like.    -   The term “benzyl” denotes the group —CH₂C₆H₅.    -   The term “carbo-C₁alkoxy” refers to an alkyl ester of a        carboxylic acid, wherein the alkyl group is C¹⁻³. Examples        include carbomethoxy, carboethoxy, carboisopropoxy and the like.    -   The term “carboxy” or “carboxyl” denotes the group —O₂H; also        referred to as a carboxylic acid.    -   The term “cyano” denotes the group —CN.    -   The term “C₃₋₆cycloalkyl” denotes a saturated ring radical        containing 3 to 6 carbons, some embodiments contain 3 to 5        carbons, and some embodiments contain 3 to 4 carbons. Examples        include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the        like.    -   The term “C₁₋₆ dialkylcarboxanido” denotes two alkyl radicals,        that are the same or different, attached to the amine of an        amide, wherein alkyl has the same definition as described        herein. Examples of a dialkylcarboxamide include        N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide and the        like.    -   The term “halo” or “halogen” denotes to a fluoro, chloro, bromo        or iodo group.    -   The term “C₁₋₆ haloalkoxy” denotes a haloalkyl, as defined        herein, that is directly attached to an oxygen to form a        difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,        pentafluoroethoxy and the like.    -   The term “C₁₋₆ haloalkyl” denotes an alkyl group, defined        herein, wherein the alkyl is substituted with one halogen up to        fully substituted represented by the formula C_(n)F_(2n+1); when        more than one halogen is present they may be the same or        different and selected from F, Cl, Br or I. Examples include        fluoromethyl, difluoromethyl, trifluoromethyl,        chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and        the like.    -   The term “C₁₋₆ haloalkylsulfinyl” denotes a haloalkyl radical        attached to a sulfoxide of the formula: —S(O)— wherein the alkyl        radical has the same definition as described herein. Examples        include trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,        2,2-difluoroethylsulfinyl and the like.    -   The term “C₁₋₆ haloalkylsulfonyl” denotes a haloalkyl attached        to a sulfone of the formula: —S(O)₂— wherein haloalkyl has the        same definition as described herein. Examples include        trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,        2,2-difluoroethylsulfonyl and the like.    -   The term “C₁₋₆ haloalkylthio” denotes an alkylthio radical        substituted with one or more halogens. Examples include        trifluoromethylthio, 1,1-difluoroethylthio,        2,2,2-trifluoroethylthio and the like.    -   The term “heteroaryl” denotes an aryl ring wherein one or more        of the ring carbons are replaced by a ring nitrogen, examples        include, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,        triazinyl, and the like.    -   The term “heterocyclyl” denotes a non-aromatic carbon ring        (i.e., cycloalkyl) where one, two or three ring carbons are        independently replaced with a heteroatom, such as, piperidinyl,        morpholinyl, piperzinyl, pyrrolidinyl, tetrahydrofuranyl and the        like.    -   The term “hydroxyl” denotes the group —OH.    -   The term “nitro” denotes the group —NO₂.    -   The term “perfluoroalkyl” denotes the group of the formula        —C_(n)F_(2n+1); stated differently, a perfluoroalkyl is an alkyl        as defined herein wherein the alkyl is fully substituted with        fluorine atoms and is therefore considered a subset of        haloalkyl. Examples of perfluoroalkyls include CF₃, CF₂CF₃,        CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃, CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃        and the like.    -   The term “thiol” denotes the group —SH.    -   The term “substituted aryl” denotes an aryl group as defined        herein that is substituted with 1, 2, 3, 4, or 5 substituents        selected from the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy,        C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido,        C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₁₋₆        dialkylamino, carbo C₁₋₆ alkoxy, carboxy, cyano, C₃₋₆        cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆ haloalkoxy,        C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl,        C₁₋₆ haloalkylthio, hydroxyl, nitro and thiol. Examples of a        substituted aryl include, but not limited to, 3-methoxyphenyl,        4-methoxyphenyl, 3,5-difluorophenyl, and the like.

COMPOSITION means a material comprising at least one component; a“pharmaceutical composition” is an example of a composition.

COMPOUND EFFICACY shall mean a measurement of the ability of a compoundto inhibit or stimulate receptor functionality; i.e. the ability toactivate/inhibit a signal transduction pathway, in contrast to receptorbinding affinity. Exemplary means of detecting compound efficacy aredisclosed in the Example section of this patent document.

CONTACT or CONTACTING shall mean bringing at least two moietiestogether, whether in an in vitro system or an in vivo system. Thus,“contacting” a RUP38 receptor with a compound of the invention includesthe administration of a compound of the present invention to anindividual, for example a human, having a RUP38 receptor, as well as,for example, introducing a compound of the invention into a samplecontaining a cellular or more purified preparation containing a RUP38receptor.

CORONARY HEART DISEASE is intended herein to encompass disorderscomprising a narrowing of the small blood vessels that supply blood andoxygen to the heart. CORONARY HEART DISEASE usually results from thebuild up of fatty material and plaque. As the coronary arteries narrow,the flow of blood to the heart can slow or stop. CORONARY HEART DISEASEcan cause chest pain (stable angina), shortness of breath, heart attack,or other symptoms.

DECREASE is used to refer to a reduction in a measurable quantity and isused synonymously with the terms “reduce”, “diminish”, “lower”, and“lessen”.

DIABETES as used herein is intended to encompass the usual diagnosis ofDIABETES made from any of the methods including, but not limited to, thefollowing list: symptoms of diabetes (e.g., polyuria, polydipsia,polyphagia) plus casual plasma glucose levels of greater than or equalto 200 mg/dl, wherein casual plasma glucose is defined any time of theday regardless of the timing of meal or drink consumption; 8 hourfasting plasma glucose levels of less than or equal to 126 mg/dl; andplasma glucose levels of greater than or equal to 200 mg/dl 2 hoursfollowing oral administration of 75 g anhydrous glucose dissolved inwater.

DISORDERS OF LIPID METABOLISM is intended herein to include, but not belimited to, dyslipidemia.

DYSLIPIDEMIA is intended herein to encompass disorders comprising anyone of elevated level of plasma free fatty acids, elevated level ofplasma cholesterol, elevated level of LDL-cholesterol, reduced level ofHDL-cholesterol, and elevated level of plasma triglycerides.

The term HYDRATE OR SOLVATE THEREOF as used herein and in the claims isintended to include hydrated forms such as monohydrate, dihydrate,hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like aswell as solvated forms. The products may be true hydrates, while inother cases, the products may merely retain adventitious water or be amixture of water plus some adventitious solvent. It should beappreciated by those skilled in the art that hydrated and/or solvatedforms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention.

The phrase IN NEED OF TREATMENT, as used herein, refers to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, etc. inthe case of humans; veterinarian in the case of animals, includingnon-human mammals) that an individual or animal requires or will benefitfrom treatment. This judgment is made based on a variety of factors thatare in the realm of a caregiver's expertise, that includes the knowledgethat the individual is ill, or will be ill, as the result of a disease,condition or disorder that is treatable by the compounds of theinvention. Further, the phrase “in need of treatment” also refers to the“prophylaxis” of an individual which is the judgment made by thecaregiver that the individual will become ill. In this context, thecompounds of the invention are used in a protective or preventivemanner. Accordingly, “in need of treatment” refers to the judgment ofthe caregiver that the individual is already ill or will become ill andthe compounds of the present invention can be used to alleviate,inhibit, ameliorate or prevent the disease, condition or disorder.

INDIRECTLY IDENTIFYING or INDIRECTLY IDENTIFIED means the traditionalapproach to the drug discovery process involving identification of anendogenous ligand specific for an endogenous receptor, screening ofcandidate compounds against the receptor for determination of thosewhich interfere and/or compete with the ligand-receptor interaction, andassessing the efficacy of the compound for affecting at least one secondmessenger pathway associated with the activated receptor.

INDIVIDUAL as used herein refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the term “response” shall meanthat a response is decreased or prevented in the presence of a compoundas opposed to in the absence of the compound.

INSULIN RESISTANCE as used herein is intended to encompass the usualdiagnosis of insulin resistance made by any of a number of methods,including but not restricted to: the intravenous glucose tolerance testor measurement of the fasting insulin level. It is well known that thereis an excellent correlation between the height of the fasting insulinlevel and the degree of insulin resistance. Therefore, one could useelevated fasting insulin levels as a surrogate marker for insulinresistance for the purpose of identifying which normal glucose tolerance(NGT) individuals have insulin resistance. A diagnosis of insulinresistance can also be made using the euglycemic glucose clamp test.

The term INVERSE AGONISTS shall mean moieties that bind the endogenousform of the receptor or to the constitutively activated form of thereceptor, and which inhibit the baseline intracellular responseinitiated by the active form of the receptor below the normal base levelof activity which is observed in the absence of agonists or partialagonists, or decrease GTP binding to membranes. In some embodiments, thebaseline intracellular response is inhibited in the presence of theinverse agonist by at least 30%, in other embodiments, by at least 50%,and in still other embodiments, by at least 75%, as compared with thebaseline response in the absence of the inverse agonist.

LIGAND shall mean a molecule specific for a naturally occurringreceptor.

METABOLIC-RELATED DISORDERS are intended herein to include, but not belimited to, dyslipidemia, atherosclerosis, coronary heart disease,insulin resistance, obesity, impaired glucose tolerance, atheromatousdisease, hypertension, stroke, Syndrome X, heart disease and type 2diabetes.

As used herein, the terms MODULATE or MODULATING shall mean to refer toan increase or decrease in the amount, quality, response or effect of aparticular activity, function or molecule.

PARTIAL AGONISTS shall mean materials (e.g., ligands, candidatecompounds) that activate the intracellular response when they bind tothe receptor to a lesser degree/extent than do full agonists.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at leastone active ingredient whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, and not limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan.

The term PHARMACEUTICALLY ACCEPTABLE CARRIER or EXCIPIENT shall mean anysubstantially inert substance used as a diluent or vehicle for acompound of the present invention.

The phrase THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology; or symptomatology of the disease, condition or disorder(i.e., arresting further development of the pathology and/orsymptomatology), and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Synthetic Methods of Benzotriazoles

The compounds of the present invention can be readily prepared accordingto a variety of synthetic regimes, all of which would be familiar to oneskilled in the art. The chemical and patent literature quotes generalprocedures for the synthesis of benzotriazoles. Some relevant referencesinclude: James, D. R. and Felix, R. A., PCT Int. Application WO9425446A1; Katritzky A. R. and Rees, C. W., Comprehensive HeterocyclicChemistry, Pergamon Press, 1996.

In the illustrated syntheses outlined below, the labeled substituentshave the same identifications as set out in the definitions of thecompound described above. As shown below, the methods describedthereafter may be used for the preparation of compound of Formula (I).

The benzotriazoles derivatives of the Formula (I) of the presentinvention may be prepared by the following exemplary general procedureas described in Reaction Scheme (1) shown below:

In this instance, the R₁ group is introduced via a displacement reactionof an ortho-halo nitrobenzene (A) with amine (B). A variety of aminescan be purchased or prepared by methods known in the art and therefore adiverse set of R₁ groups may be introduced, see below for furtherdiscussion. Intermediate (C) can be converted to diamino (D) by avariety of reducing methods, such as, tin under acidic conditions,alcoholic ammonium sulfide with heat, hydrogen in the presence of Pd/C,iron or SnCl₂. The resulting ortho phenylenediamine can be readilycyclized to the compounds of Formula (I) by treatment with nitrite, suchas NaNO₂ or isoamyl nitrite in the presence of an acid.

As mentioned, a variety of R₁ may be introduced into compounds of thepresent invention via an appropriate amine. A variety of these aminesare commercially available or readily prepared by methods known in theart. For example, R₁ may be a haloalkyl, some exemplary haloalkyl aminesinclude, 1,1,1,3,3,3-hexafluoro-2-amino-propane and1,1,1,2,3,3,3-heptafluoro-2-amino-propane and can be prepared from thereadily available hexafluoroacetone by the methods described byMiddleton and co-workers in J. Org. Chem., 1965, 30, 1398-1402. Otheramines include 2,2,2-trifluoroethylamine,3,3,3,2,2-pentafluoropropylamine, 3,3,3-trifluoropropylamine, and thelike. Similarly, R₁ may be a cycloalkyl and in accordance with ReactionScheme (I) a number of cycloalkyl groups may be introduced using thismethod. For example, cyclopropyl amine, cyclobutyl amine, cyclopentylamine and cyclohexyl amine may be utilized to afford compounds ofFormula (I). In the example where R₁ is a cyclopropyl group an analogousdisplacement step in Reaction Scheme (I) has been reported in theliterature by Cecchetti, A. and co-workers in J. Med. Chem. 1995, 38,973-982; a similar reaction has also been reported for cyclopentyl amineby Pan, P-C and Sun, C-M in Bioorg, Med. Chem. Lett. 1999, 9, 1537-1540.In addition, a variety of substituted cycloalkyl amines are commerciallyavailable or may be prepared by methods known in the art, for example, avariety of cyclopropyl amines may be prepared from a nitrile and aGrignard reagent in the presence of a reagent such as, Ti(i-OPr)₄, andfollowed by treatment with BF₃.Et₂O (Bertus, P. and Szymoniak, J. inChem. Comm. 2001, 18, 1792-1793). Other methods are known for thepreparation of cycloalkyl amines and substituted cycloalkyl amines.

An alternative method for the preparation of compounds of Formula (I) isshown in Reaction Scheme (2):

This method may utilize a variety of anilines as starting materials.These anilines may be converted into intermediate CE) by methods knownin the art, such as, alkylation, reductive amination and the like.Subsequently, intermediate (E) may be nitrated to give intermediate (C)and the remaining steps in Reaction Scheme (2) are similar to thosedescribed above in Reaction Scheme (1).

The various organic group transformations utilized herein may beperformed through a number of procedures other than those describedabove. References for other synthetic procedures that may be utilizedfor the preparation of intermediates or compounds disclosed herein maybe found in, for example, Smith, M. B.; and March, J., Advanced OrganicChemistry, 5^(th) Edition, Wiley-Interscience (2001); Larock, R. C.,Comprehensive Organic Transformations, A Guide to Functional GroupPreparations, 2^(nd) Edition, VCH Publishers, Inc. (1999), or Wuts, P.G. M.; Greene, T. W.; Protective Groups in Organic Synthesis, 3^(rd)Edition, John Wiley and Sons, (1999), all three incorporated herein byreference.

Representative examples are shown below in Tables B and C. TABLE BWherein R₁ is a cyclopropyl (i.e., cC₃H₅—) or cyclobutyl (cC₄H₇—)radical (I)

R₁ R₂ R₃ R₄ cC₃H₅— H H H cC₃H₅— H H F cC₃H₅— H F H cC₃H₅— F H H cC₃H₅— HF F cC₃H₅— F H F cC₃H₅— F F H cC₃H₅— F F F cC₃H₅— H H Cl cC₃H₅— H Cl HcC₃H₅— Cl H H cC₄H₇— H H H cC₄H₇— H H F cC₄H₇— H F H cC₄H₇— F H H cC₄H₇—H F F cC₄H₇— F H F cC₄H₇— F F H cC₄H₇— F F F cC₄H₇— H H Cl cC₄H₇— H Cl HcC₄H₇— Cl H H

TABLE C Where R₁ is a 2,2,2-trifluoroethyl or1-(2,2,2-Trifluoro-1-trifluoromethyl- ethyl) group (I)

R₁ R₂ R₃ R₄ CF₃CH₂— H H H CF₃CH₂— H H F CF₃CH₂— H F H CF₃CH₂— F H HCF₃CH₂— H F F CF₃CH₂— F H F CF₃CH₂— F F H CF₃CH₂— F F F CF₃CH₂— H H ClCF₃CH₂— H Cl H CF₃CH₂— Cl H H (CF₃)₂CH— H H H (CF₃)₂CH— H F H (CF₃)₂CH—F H H (CF₃)₂CH— H F F (CF₃)₂CH— F H F (CF₃)₂CH— F F H (CF₃)₂CH— F F F(CF₃)₂CH— H H Cl (CF₃)₂CH— H Cl H (CF₃)₂CH— Cl H H

Additionally, compounds of Formula (I) encompass all pharmaceuticallyacceptable solvates, particularly hydrates, thereof. The presentinvention also encompasses diastereomers as well as optical isomers,e.g. mixtures of enantiomers including racemic mixtures, as well asindividual enantiomers and diastereomers, which arise as a consequenceof structural asymmetry in certain compounds of Formula (I). Separationof the individual isomers or selective synthesis of the individualisomers is accomplished by application of various methods which are wellknown to practitioners in the art.

Pharmaceutical Compositions

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are available to those in the art; for example, seeRemington's Pharmaceutical Sciences, 16^(th) Edition, 1980, MackPublishing Co., (Oslo et al., eds.) or a more recent edition thereof.

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may in an alternative use be administered as araw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable therapeutically effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

The dose when using the compounds of Formula (I) can vary within widelimits, and as is customary and is known to the physician, it is to betailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the Formula (I). Representative doses ofthe present invention include, about 0.01 mg to about 1000 mg, about0.01 to about 750 mg, about 0.01 to about 500 mg, 0.01 to about 250 mg,0.01 mg to about 200 mg, about 0.01 mg to 150 mg, about 0.01 mg to about100 mg, and about 0.01 mg to about 75 mg. Multiple doses may beadministered during the day, especially when relatively large amountsare deemed to be needed, for example 2, 3 or 4, doses. If appropriate,depending on individual behavior and as appropriate from the patientsphysician or care-giver it may be necessary to deviate upward ordownward from the daily dose.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. Typically, animal modelsinclude, but are not limited to, the rodent diabetes models as describedin Example 1, infra, or the mouse arthrosclerosis model as described inExample 2, infra. In some circumstances, these extrapolations may merelybe based on the weight of the animal model in comparison to another,such as a mammal, preferably a human, however, more often, theseextrapolations are not simply based on weights, but rather incorporate avariety of factors. Representative factors include the type, age,weight, sex, diet and medical condition of the patient, the severity ofthe disease, the route of administration, pharmacological considerationssuch as the activity, efficacy, pharmacolinetic and toxicology profilesof the particular compound employed, whether a drug delivery system isutilized, on whether an acute or chronic disease state is being treatedor prophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the Formula (I) and as partof a drug combination. The dosage regimen for treating a diseasecondition with the compounds and/or compositions of this invention isselected in accordance with a variety factors as cited above. Thus, theactual dosage regimen employed may vary widely and therefore may deviatefrom a preferred dosage regimen and one skilled in the art willrecognize that dosage and dosage regimen outside these typical rangescan be tested and, where appropriate, may be used in the methods of thisinvention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms, as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of theFormula (I) or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the Formula (I) as an aerosol can be prepared by processeswell-known to the person skilled in the art. For their preparation, forexample, solutions or dispersions of the compounds of the Formula (I) inwater, water/alcohol mixtures or suitable saline solutions can beemployed using customary additives, for example benzyl alcohol or othersuitable preservatives, absorption enhancers for increasing thebioavailability, solubilizers, dispersants and others, and, ifappropriate, customary propellants, for example include carbon dioxide,CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference.

Combination Therapy/Prophylaxis

While the compounds of the invention can be administered as the soleactive pharmaceutical agent as described herein above, they can also beused in combination with one or more agents belonging to the class ofdrugs known as α-glucosidase inhibitors, aldose reductase inhibitors,biguanides, IBG-CoA reductase inhibitors, squalene synthesis inhibitors,fibrate compounds, LDL catabolism enhancers and angiotensin convertingenzyme (ACE) inhibitors.

α-Glucosidase inhibitors belong to the class of drugs whichcompetitively inhibit digestive enzymes such as α-amylase, maltase,α-dextrinase, sucrase, etc. in the pancreas and or small intestine. Thereversible inhibition by α-glucosidase inhibitors retard, diminish orotherwise reduce blood glucose levels by delaying the digestion ofstarch and sugars. Some representative examples of α-glucosidaseinhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(generic name; voglibose), miglitol, and α-glucosidase inhibitors knownin the art.

The class of aldose reductase inhibitors are drugs which inhibit thefirst-stage rate-limiting enzyme in the polyol pathway that prevent orarrest diabetic complications. In the hyperglycemic state of diabetes,the utilization of glucose in the polyol pathway is increased and theexcess sorbitol accumulated intracellularly as a consequence acts as atissue toxin and hence evokes the onset of complications such asdiabetic neuropathy, retinopathy, and nephropathy. Examples of thealdose reductase inhibitors include tolurestat; epalrestat;3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid;2,7-difluorospiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione (genericname: imirestat);3-[(4-bromo-2-flurophenyl)methy]-7-chloro-3,4-dihydro-2,4-dioxo-[(2H)-quinazolineacetic acid (generic name: zenarestat);6-fluoro-2,3-dihydro-2′,5′-dioxo-spiro[4H-1-benzopyran-4,4′-imidazolidine]-2-carboxamide(SNK-860); zopolrestat; sorbinil; and1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209),and aldose reductase inhibitors known in the art.

The biguanides are a class of drugs that stimulate anaerobic glycolysis,increase the sensitivity to insulin in the peripheral tissues, inhibitglucose absorption from the intestine, suppress of hepaticgluconeogenesis, and inhibit fatty acid oxidation. Examples ofbiguanides include phenformin, metformin, buformin, and biguanides knownin the art.

Statin compounds belong to a class of drugs that lower blood cholesterollevels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase.HMG-CoA reductase is the rate-limiting enzyme in cholesterolbiosynthesis. A statin that inhibits this reductase lowers serum LDLconcentrations by upregulating the activity of LDL receptors andresponsible for clearing LDL from the blood. Examples of the statincompounds include rosuvastatin, pravastatin and its sodium salt,simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, andHMG-CoA reductase inhibitors known in the art.

Squalene synthesis inhibitors belong to a class of drugs that lowerblood cholesterol levels by inhibiting synthesis of squalene. Examplesof the squalene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, mono potassium salt BMS-188494) and squalene synthesis inhibitorsknown in the art.

Fibrate compounds belong to a class of drugs that lower bloodcholesterol levels by inhibiting synthesis and secretion oftriglycerides in the liver and activating a lipoprotein lipase. Fibrateshave been known to activate peroxisome proliferators-activated receptorsand induce lipoprotein lipase expression. Examples of fibrate compoundsinclude bezafibrate, beclobrate, binifibrate, ciplofibrate,clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate,gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate,theofibrate, and fibrates known in the art.

LDL (low-density lipoprotein) catabolism enhancers belong to a class ofdrugs that lower blood cholesterol levels by increasing the number ofLDL (low-density lipoprotein) receptors, examples include LDL catabolismenhancers known in the art.

Angiotensin converting enzyme (ACE) inhibitors belong to the class ofdrugs that partially lower blood glucose levels as well as loweringblood pressure by inhibiting angiotensin converting enzymes. Examples ofthe angiotensin converting enzyme inhibitors include captopril,enalapril, alacepril, delapril; raripril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and angiotensin converting enzyme inhibitors known in theart.

Insulin secretion enhancers belong to the class of drugs having theproperty to promote secretion of insulin from pancreatic β cells.Examples of the insulin secretion enhancers include sulfonylureas (SU).The sulfonylureas (SU) are drugs which promote secretion of insulin frompancreatic β cells by transmitting signals of insulin secretion via SUreceptors in the cell membranes. Examples of the sulfonylureas includetolbutamide; chlorpropamide; tolazamide; acetohexamide;4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benzenesulfonamide (genericname: glycopyramide) or its ammonium salt; glibenclamide (glyburide);gliclazide; 1-butyl-3-metanilylurea; carbutamide; glibonuride;glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole;glyhexamide; glymidine; glypinamide; phenbutamide; tolcyclamide,glimepiride, and other insulin secretion enhancers known in the art.Other insulin secretion enhancers includeN-[[4-(1-methylethyl)cyclohexyl)carbonyl]-D-phenylalanine (Nateglinide);calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionatedihydrate (Mitiglinide, KAD-1229); and other insulin secretion enhancersknown in the art.

Thiazolidinediones belong to the class of drugs more commoningly knownas TZDs. Examples of thiazolidinediones include rosiglitazone,pioglitazone, and thiazolidinediones known in the art.

Some embodiments of the invention include, a pharmaceutical compositioncomprising a compound of Formula (I) or a pharmaceutically acceptablesalt thereof in combination with at least one member selected from thegroup consisting of an α-glucosidase inhibitor, an aldose reductaseinhibitor, a biguanide, a HMG-CoA reductase inhibitor, a squalenesynthesis inhibitor, a fibrate compound, a LDL catabolism enhancer andan angiotensin converting enzyme inhibitor. In another embodiment, thepharmaceutical composition is a compound of Formula (I) or apharmaceutically acceptable salt thereof in combination with a HMG-CoAreductase inhibitor. In still another embodiment, the HMG-CoA reductaseinhibitor is selected from the group consisting of prevastatin,simvastatin, lovastatin, atorvastatin, fluvastatin and lipitor.

In accordance with the present invention, the combination can be used bymixing the respective active components either all together orindependently with a physiologically acceptable carrier, excipient,binder, diluent, etc., as described herein above, and administering themixture or mixtures either orally or non-orally as a pharmaceuticalcomposition. When a compound or a mixture of compounds of Formula (I)are administered as a combination therapy or prophylaxis with anotheractive compound the therapeutic agents can be formulated as a separatepharmaceutical compositions given at the same time or at differenttimes, or the therapeutic agents can be given as a single composition.

Labeled Compounds and Assay Methods

Another object of the present invention relates to radio-labeledcompounds of Formula (1) that are useful not only in radio-imaging butalso in assays, both in vitro and in vivo, for localizing andquantitating hRUP38 in tissue samples, including human, and foridentifying hRUP38 ligands by inhibition binding of a radio-labeledcompound. It is a further object of this invention to include novelhRUP38 assays of which comprise such radio-labeled compounds.

The present invention embraces isotopically-labeled compounds of Formula(I) and any subgenera herein, such as but not limited to, Formulae (Ia)to (Is). An “isotopically” or “radio-labeled” compounds are those whichare identical to compounds disclosed herein, but for the fact that oneor more atoms are replaced or substituted by an atom having an atomicmass or mass number different from the atomic mass or mass numbertypically found in nature (i.e., naturally occurring). Suitableradionuclides that can be incorporated in compounds of the presentinvention include but are not limited to ²H (also written as D fordeuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N ¹⁵N,¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and¹³¹I. The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro hRUP38 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S orwill generally be most useful. For radio-imaging applications ¹¹C, ¹⁸F,¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be mostuseful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (I) that has incorporated at least one radionuclide;in some embodiments the radionuclide is selected from the groupconsisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence can be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the scarcer radio-isotope or nonradio-activeisotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, and are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]—This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled hRUP38 compound of Formula (I) can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (I)” to the hRUP38 receptor. Accordingly, theability of a test compound to compete with the “radio-labeled compoundof Formula (I)” for the binding to the hRUP38 receptor directlycorrelates to its binding affinity.

The labeled compounds of the present invention bind to the hRUP38receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM, and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES

The following examples are presented for purposes of elucidation, andnot limitation, of the present invention. One of ordinary skill in theart would be able to design equivalent assays and methods based on thedisclosure herein, all of which form part of the present invention.

Example 1

Rodent Diabetes Models

Rodent models of type 2 diabetes associated with obesity and insulinresistance have been developed. Genetic models such as db/db and ob/ob[see Diabetes (1982) 31:1-6] in mice and fa/fa in zucker rats have beendeveloped for understanding the pathophysiology of disease and fortesting candidate therapeutic compounds [Diabetes (1983) 32:830-838;Annu Rep Sankyo Res Lab (1994) 46:1-57]. The homozygous animals, C57BL/KsJ-db/db mice developed by Jackson Laboratory are obese,hyperglycemic, hyperinsulinemic and insulin resistant [J Clin Invest(1990) 85:962-967], whereas heterozygotes are lean and normoglycemic. Inthe db/db model, mice progressively develop insulinopenia with age, afeature commonly observed in late stages of human type 2 diabetes whensugar levels are insufficiently controlled. Since this model resemblesthat of human type 2 diabetes, the compounds of the present inventionare tested for activities including, but not limited to, lowering ofplasma glucose and triglycerides. Zucker (fa/fa) rats are severelyobese, hyperinsulinemic, and insulin resistant {Coleman, Diabetes (1982)31:1; E Shafrir in Diabetes Mellitus, H Rifkin and D Porte, Jr, Eds[Elsevier Science Publishing Co, New York, ed. 4, (1990), pp. 299-340]},and the fa/fa mutation may be the rat equivalent of the murine dbmutation [Friedman et al, Cell (1992) 69:217-220; Truett et al, ProcNatl Acad Sci USA (1991) 88:7806]. Tubby (tub/tub) mice arecharacterized by obesity, moderate insulin resistance andhyperinsulinemia without significant hyperglycemia [Coleman et al,Heredity (1990) 81:424).

The present invention encompasses the use of compounds of the inventionfor reducing the insulin resistance and hyperglycemia in any or all ofthe above rodent diabetes models, in humans with type 2 diabetes orother preferred metabolic-related disorders or disorders of lipidmetabolism described previously, or in models based on other mammals.Plasma glucose and insulin levels will be tested, as well as otherfactors including, but not limited to, plasma free fatty acids andtriglycerides.

In Vivo Assay for Anti-Hyperglycemic Activity of Compounds of theInvention

Genetically altered obese diabetic mice (db/db) (male, 7-9 weeks old)are housed (7-9 mice/cage) under standard laboratory conditions at 22°C. and 50% relative humidity, and maintained on a diet of Purina rodentchow and water ad libitum. Prior to treatment, blood is collected fromthe tail vein of each animal and blood glucose concentrations aredetermined using One Touch Basic Glucose Monitor System (Lifescan). Micethat have plasma glucose levels between 250 to 500 mg/dl are used. Eachtreatment group consists of seven mice that are distributed so that themean glucose levels are equivalent in each group at the start of thestudy db/db mice are dosed by micro-osmotic pumps, inserted usingisoflurane anesthesia, to provide compounds of the invention, saline, oran irrelevant compound to the mice subcutaneously (s.c.). Blood issampled from the tail vein at intervals thereafter and analyzed forblood glucose concentrations. Significant differences between groups(comparing compounds of the invention to saline-treated) are evaluatedusing Student t-test.

Example 2

Mouse Atherosclerosis Model

Adiponectin-deficient mice generated through knocking out theadiponectin gene have been shown to be predisposed to atherosclerosisand to be insulin resistant. The mice are also a suitable model forischemic heart disease [Matsuda, M et al. J Biol Chem (2002) July, andreferences cited therein, the disclosures of which are incorporatedherein by reference in their entirety].

Adiponectin knockout mice are housed (7-9 mice/cage) under standardlaboratory conditions at 22° C. and 50% relative humidity. The mice aredosed by micro-osmotic pumps, inserted using isoflurane anesthesia, toprovide compounds of the invention, saline, or an irrelevant compound tothe mice subcutaneously (s.c.). Neointimal thickening and ischemic heartdisease are determined for different groups of mice sacrificed atdifferent time intervals. Significant differences between groups(comparing compounds of the invention to saline-treated) are evaluatedusing Student t-test.

Example 3

Inhibition of Isoproterenol Stimulated Lipolysis in Human SubcutaneousAdipocytes

Nicotinic acid and 1-Isopropyl-1H-benzotriazole-5-carboxylic acid wereseparately dose-dependently applied to isoproterenol (100 nM) stimulatedprimary human adipocytes. FIG. 2 illustrates the ability of1-Isopropyl-1H-benzotriazole-5-carboxylic acid to inhibit isoproterenolstimulated lipolysis in adipocyte primary cultures derived from humansubcutaneous fat in a dose-dependent manner comparable to that ofnicotinic acid.

Example 4

In Vitro Biological Activity

A modified Flash Plate™ Adenylyl Cyclase kit (New England Nuclear; Cat.No. SMP004A) was utilized for direct identification of candidatecompounds as agonists to hRUP38 (Seq. Id. Nos. 1 & 2) or hRUP25 (Seq.Id. Nos. 3 & 4) in accordance with the following protocol:

CHO cells stably transfected with hRUP38 were harvested from flasks vianon-enzymatic means. The cells were washed in PBS and resuspended in themanufacturer's Assay Buffer. Live cells were counted using ahemacytometer and Trypan blue exclusion, and the cell concentration wasadjusted to 2×10⁶ cells/ml. cAMP standards and Detection Buffer(comprising 2 μCi of tracer [¹²⁵I]-cAMP (100 μl) to 11 ml DetectionBuffer) were prepared and maintained in accordance with themanufacturer's instructions. Candidate compounds identified as per above(if frozen, thawed at room temperature) were added to their respectivewells (preferably wells of a 96-well plate) at increasing concentrations(3 μl/well; 12 μM final assay concentration). To these wells, 100,000cells in 50 μl of Assay Buffer were added and the mixture was thenincubated for 30 minutes at room temperature, with gentle shaking.Following the incubation, 100 μl of Detection Buffer was added to eachwell, followed by incubation for 2-24 hours. Plates were counted in aWallac MicroBeta™ plate reader using “Prot. #31” (as per manufacturerinstructions).

Example 5 Representative Biological Activity

The biological in vitro activity was determined using the cAMP WholeCell method, one representative example is shown in the table below:hRUP38 (EC₅₀) Compound cAMP Whole Cell (nM) Example 6.1 388**Value is an average of seven (7) trials.

Certain compounds in the Examples showed below display EC₅₀ activitiesin the cAMP Whole Cell (nM) assay of less than about 25 μM.

Example 6.1 Preparation of 1-Isopropyl-1H-benzotriazole-5-carboxylicacid

4-Isopropylamino-3-nitro-benzoic acid (0.077 g, 0.34 mmol) was taken upin ethyl acetate (30 mL), palladium (10% on carbon, 0.010 g) added andthe suspension shaken at room temperature under a hydrogen atmosphere(balloon pressure) for 3 hours. The resulting solution was filteredthrough celite and solvent removed under reduced pressure to give3-amino-4-ethylamino-benzoic acid as a pale brown glass. The diamine wastaken up immediately in glacial acetic acid (5 mL), and polymersupported nitrate (0.030 g, loading ca 4 mmolg⁻¹, 0.12 mmol) added. Themixture was shaken overnight at room temperature under argon, filteredand solvent removed under reduced pressure to give1-isopropyl-1H-benzotriazole-5-carboxylic acid as a brown crystallinesolid (0.057 g, 0.28 mmol, 81%). m/z (ES⁺): 206 [M+H]⁺. ¹H NMR (CD₃OD):8.58 (s, 1H, C(4)-H), 8.09 (dd, 1H, J₁=8.8, J₂=1.4, C(6)-H), 7.79 (dd,1H, J₁=8.8, J₂=0.5, C(7)-H), 5.15 (septet, 1H, J=6.7, CH(CH₃)₂), 1.63(d, 6H, J=6.7, CH(CH ³ )₂).

The intermediate 4-isopropylamino-3-nitro-benzoic acid was prepared inthe following manner:

a. 4-Isopropylamino-3-nitro-benzoic acid

A mixture of 4-fluoro-3-nitrobenzoic acid (100 mg, 0.541 mmol),isopropyl amine (40 mg, 0.678) and sodium bicarbonate (0.10 g, 1.2 mmol)in H₂O (3 mL) was heated to 150° C. for 20 minutes under microwaveirradiation. The resulting orange mixture was cooled, poured into 1 NHCl (40 mL) and extracted into EtOAc. The solvent was removed underreduced pressure to (4-isopropylamino-3-nitro-benzoic acid as a yellowsolid which was used without further purification. ¹H NMR (CDCl₃) δ 9.05(d, J=2.0 Hz, 1H), 8.47, (d, J=6.5 Hz, 1H), 8.16 (dd, J₁=9.1 Hz, J₂=2.0Hz, 1H), 7.00 (d, J=9.1 Hz, 1H), 4.01 (septet, J=6.5 Hz, 1H), 1.47 (d,J=6.5 Hz, 6H).

Example 6.2 Preparation of 1-Cyclopentyl-1H-benzotriazole-5-carboxylicacid

1-Cyclopentyl-1H-benzotriazole-5-carboxylic acid was prepared in asimilar as described in Example 6.1 using4-cyclopentylamino-3-nitro-benzoic acid as the intermediate. m/z (ES⁺):232 [M+H]⁺. ¹H NMR (CD₃OD): 8.67 (dd, 1H, J₁=1.3, J₂=0.7, C(4)-H, 8.19(dd, 1H, J₁=8.8, J₂=1.3, C(6)-H), 7.87 (dd, 1H, J₁=8.8, J₂=0.7, C(7)-H),5.45-5.30 (m, 1H, NCH, 2.45-2.20 (m, 4H), 2.10-1.95 (m, 2H), 1.95-1.80(m, 2H).

The intermediate 4-cyclopentylamino-3-nitro-benzoic acid was prepared ina manner as described in Example 6.1 a. using cyclopentylamine. ¹H NMR(CD₃OD): 8.81 (d, 1H, J=2.1, C(2)-H), 8.06 (dd, 1H, J₁=9.1, J₂=2.1,C(6)-H, 7.12 (d, 1H, J=9.1, C(5)-H), 4.2-4.1 (m, 1H, NHCH), 2.3-2.1 (m,2H), 1.9-1.6 (m, 6H).

Example 6.3 Preparation of 1-(2′-Butyl)-1H-benzotriazole-5-carboxylicacid

1-(2′-Butyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar as described in Example 6.1 using4-(2′-butyl)amino-3-nitro-benzoic acid. m/z (ES⁺): 220 [M+H]⁺. ¹H NMR(CD₃OD): 8.72 (dd, 1H, J₁=1.3, J₂=0.7, C(4)-H), 8.22 (dd, 1H, J=8.8,J₂=1.3, C(6)-H), 7.91 (dd, 1H, J₁=8.8, J₂=0.7, C(7)-H, 5.10-5.00 (m, 1H,NCH), 2.30-2.05 (m, 2H, CH ² CH₃), 1.75 (d, 3H, J=6.8, CHCH ³ ), 0.85(t, 3H, J=7.4, CH₂CH₃).

The intermediate 4-(2′-butyl)amino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using 2-butylamine. ¹HNMR (CD₃OD): 8.81 (d, 1H, J=2.1, C(2)-H, 8.04 (dd, 1H, J₁=9.2, J₂=2.1,C(6)-H), 7.10 (d, 1H, J=9.2, C(5)-H), 3.82 (sextet like, 1H, J=6.4,NHCH), 1.75-1.65 (m, 2H, CH ² CH₃), 1.31 (d, 3H, J=6.4, CHCH ³ ), 1.02(t, 3H, J=7.5, CH₂CH ³ ).

Example 6.4 Preparation of 1-(3′-Pentyl)-1H-benzotriazole-5-carboxylicacid

1-(3′-Pentyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-(3′-Pentyl)amino-3-nitro-benzoic acid. m/z (ES+): 234 [M+H]+. ¹H NMR(CD₃OD): 8.51 (dd, 1H, J1=1.4, J2=0.6, C(4)-H), 8.00 (dd, 1H, J1=8.8,J2=1.4, C(6)-H), 7.69 (dd, 1H, J1=8.8, J2=0.6, C(7)-H), 4.60 (septetlike, 1H, 3=4.8, NCH), 2.10-1.85 (m, 4H, CH2CH3), 0.58 (t, 6H, J=7.4,CH2CH3).

The intermediate 4-(3′-pentyl)amino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using 3-pentylamine. ¹HNMR (CDCl3): 8.90 (d, 1H, J=2.1, C(2)-H), 8.35 (d, 1H, J=8.2, NH), 7.98(dd, 1H, J1=9.2, J2=1.8, C(6)-H), 6.83 (d, 1H, J=9.2, C(5)-H), 3.50(sextet like, 1H, J=7.6, NHCH), 1.75-1.50 (m, 4H, CH2CH3), 0.92 (t, 6H,J=7.4, CH2CH3).

Example 6.5 Preparation of 1-Cyclohexyl-1H-benzotriazole-5-carboxylicacid

1-Cyclohexyl-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-cyclohexylamino-3-nitro-benzoic acid. m/z (ES+): 246 [M+H]+. ¹H NMR(CD₃OD): 8.67 (s, 1H, C(4)-H), 8.19 (dd, 1H, J1=8.8, J2=1.4, C(6)-H),7.90 (d, 1H, J=8.8, C(7)-H), 4.95-4.80 (m, 1H, NCH), 2.25-2.05 (m, 4H),2.05-1.95 (m, 2H), 1.90-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.50-1.40 (m,1H).

The intermediate 4-Cyclohexylamino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using cyclohexylamine.¹H NMR (CD₃OD): 8.80 (d, 1H, J=2.1, C(2)-H), 8.03 (dd, 1H, J1=9.2,J2=2.1, C(6)-H), 7.10 (d, 1H, J=9.2, C(S)-H), 3.75-3.65 (m, 1H, NHCH),2.10-2.05 (m, 2H), 1.85-1.75 (m, 2H), 1.75-1.60 (m, 1H), 1.60-1.30 (m,5H).

Example 6.6 Preparation of 1-Benzyl-1H-benzotriazole-5-carboxylic acid

1-Benzyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.1 using 4-benzylamino-3-nitro-benzoicacid. m/z (ES+): 254 [M+H]+. ¹H NMR (CD₃OD): 8.59 (dd, 1H, J1=1.3,J2=0.7, C(4)-H), 8.04 (dd, 1H, J1=8.8, J2=1.3, C(6)-H), 7.62 (dd, 1H,J1=8.8, J2=0.7, C(7)-H), 5.87 (d, 2H, NCH2).

The intermediate 4-benzylamino-3-nitro-benzoic acid was prepared in asimilar manner as described in Example 6.1 a. using benzylamine. ¹H NMR(CDCl3): 9.00 (d, 1H, J=2.0, C(2)-H), 8.79 (t, 1H, J=5.5, NH), 8.06 (dd,1H, J1=9.1, J2=1.8, C(6)-H), 7.5-7.3 (m, 5H), 6.89 (d, 1H, J=9.1,C(5)-H), 4.63 (d, 2H, NHCH2).

Example 6.7 Preparation of 1-Propyl-1H-benzotriazole-5-carboxylic acid

1-Propyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.1 using 4-propylamino-3-nitro-benzoicacid. m/z (ES+): 206 [M+H]+. ¹H NMR (CD₃OD): 8.69 (dd, 1H, J1=1.4,J2=0.7, C(4)-H), 8.20 (dd, 1H, J1=8.8, J2=1.4, C(6)-H), 7.86 (dd, 1H,J1=8.8, J2=0.7, C(7)-H), 4.73 (t, 2H, J=7.0, NCH2), 2.06 (sextet like,2H, J=7.2, CH2CH3), 0.96 (t, 3H, J=7.4, CH2CH3).

The intermediate 4-propylamino-3-nitro-benzoic acid was prepared in asimilar manner as described in Example 6.1 a. using 1-propylamine. ¹HNMR (CD₃OD): 8.80 (d, 1H, J=2.1, C(2)-H), 8.04 (dd, 1H, J1=9.1, J2=2.1,C(6)-H), 7.07 (d, 1H, J=9.1, C(5)-H), 3.40 (t, 2H, J=7.1, NHCH2), 1.76(sextet like, 2H, J=7.3, CH2CH3), 1.06 (t, 3H, J=7.4, CH2CH3).

Example 6.8 Preparation of 1-Cyclopropyl-1H-benzotriazole-5-carboxylicacid

1-Cyclopropyl-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-cyclopropylamino-3-nitro-benzoic acid. m/z (ES+): 204 [M+H]+. ¹H NMR(CD₃OD): 8.67 (dd, 1H, 31=1.4, J2=0.7, C(4)-H), 8.23 (dd, 1H, J1=8.7,J2=1.4, C(6)-H), 7.92 (dd, 1H, J1=8.7, J2=0.7, C(7)-H), 4.05-3.95 (m,1H, NCH), 1.4-1.3 (m, 4H).

The intermediate 4-cyclopropylamino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using cyclopropylamine.¹H NMR (CD₃OD): 8.78 (d, 1H, J=2.0, C(2)-H), 8.09 (dd, 1H, J1=9.0,J2=2.0, C(6)-H), 7.47 (d, 1H, J=9.0, C(5)-H), 2.71 (septet like, 1H,J=3.5, NHCH), 1.05-0.95 (m, 2H), 0.75-0.65 (m, 21).

Example 6.9 Preparation of1-(3′-Isopropoxy-propyl)-1H-benzotriazole-5-carboxylic acid

1-(3′-Isopropoxy-propyl)-1H-benzotriazole-5-carboxylic acid was preparedin a similar manner as described in Example 6.1 using4-(3′-isopropoxy-propyl)amino-3-nitro-benzoic acid. m/z (ES+): 264[M+H]+. ¹H NMR (CD₃OD): 8.68 (dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.20 (dd,1H, J1=8.8, J2=1.4, C(6)-H), 7.86 (dd, 1H, J1=8.8, J2=0.7, C(7)-H), 4.85(t, 2H, NCH2), 3.49 (septet, 1H, J=6.1, CH(CH3)2), 3.41 (t, 2H, J=5.8,CH2O), 2.25 (quintet like, 2H, J=5.9, CH2CH2CH2), 1.07 (d, 6H, J=6.1,CH(CH3)2).

The intermediate 4-(3′-isopropoxy-propyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using3-isopropoxypropyl amine. ¹H NMR (CD₃OD): 8.80 (d, 1H, J=2.1, C(2)-H),8.04 (dd, 1H, J1=9.1, J2=2.1, C(6)-H), 7.09 (d, 1H, J=9.1, C(5)-H),3.65-3.55 (m, 3H, NHCH2 & CH(CH3)2), 3.53 (t, 2H, J=6.5, CH2O), 1.97(quintet like, 2H, J=6.1, CH2CH2CH2), 1.18 (d, 6H, J=6.1, CH(CH3)2).

Example 6.10 Preparation of1-(Tetrahydro-furan-2′-ylmethyl)-1H-benzotriazole-5-carboxylic acid.

1-(Tetrahydro-furan-2′-ylmethyl)-1H-benzotriazole-5-carboxylic acid wasprepared in a similar manner as described in Example 6.1 using4-(tetrahydro-furan-2′-ylmethyl)amino-3-nitro-benzoic acid. m/z (ES+):248 [M+H]+. ¹H NMR (CD₃OD): 8.67 (s, 1H, C(4)-H), 8.18 (dd, 1H, J1=8.7,J2=1.4, C(6)-H), 7.90 (dd, 1H, J1=8.8, J2=0.4, C(7)-H), 4.95-4.85 (m,1H), 4.79 (dd, 1H, J1=14.6, J2=6.5), 4.42 (ddd, 1H, J1=13.4, J2=6.6,J3=3.6), 3.80-3.60 (m, 2H), 2.20-2.05 (m, 1H0, 1.95-1.55 (m, 3H).

The intermediate 4-(tetrahydro-furan-2′-ylmethyl)amino-3-nitro-benzoicacid was prepared in a similar manner as described in Example 6.1 a.using tetrahydro-furan-2-ylmethyl)amine. ¹H NMR (CD₃OD): 8.78 (d, 1H,J=2.1, C(2)-H), 8.03 (dd, 1H, J1=9.1, J2=2.1, C(6)-H), 7.11 (d, 1H,J=9.1, C(5)-H), 4.25-4.15 (m, 1H), 3.91 (dd, 1H, J1=15.0, J2=6.7), 3.79(dd, 1H, J1=13.9, J2=7.0), 3.58 (dd, 1H, J1=13.5, J2=3.8), 3.42 (dd, 1H,J1=13.5, J2=7.0), 2.15-2.05 (m, 1H0, 2.05-1.85 (m, 2H), 1.80-1.70 (m,1H).

Example 6.11 Preparation of 1-Cyclobutyl-1H-benzotriazole-5-carboxylicacid

1-Cyclobutyl-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-cyclobutylamino-3-nitro-benzoic acid. m/z (ES+): 218 [M+H]+. ¹H NMR(CD₃OD): 8.68 (dd, 1H, J1=1.4, J2=0.6, C(4)-H), 8.19 (dd, 1H, J1=8.8,J2=1.4, C(6)-H), 7.86 (dd, 1H, J1=8.8, J2=0.6, C(7)-H), 5.46 (quintetlike, 1H, J=8.3, NCH), 2.95-2.80 (m, 2H), 2.80-2.65 (m, 2H), 2.15-2.05(m, 2H).

The intermediate 4-cyclobutylamino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using cyclobutylamine.¹H NMR (CD₃OD): 8.78 (d, 1H, J=2.0, C(2)-H), 8.03 (dd, 1H, J1=9.0,J2=2.0, C(6)-H), 6.93 (d, 1H, J=9.0, C(5)-H), 4.22 (quintet like, 1H,J=7.8, NHCH), 2.60-2.50 (m, 2H), 2.15-2.00 (m, 2H), 2.00-1.85 (m, 2H).

Example 6.12 Preparation of1-(2-Methoxy-ethyl)-1H-benzotriazole-5-carboxylic acid

1-(2-Methoxy-ethyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-(2′-methoxy-ethyl)amino-3-nitro-benzoic acid. m/z (ES+): 222 [M+H]+.¹H NMR (CD₃OD): 8.67 (dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.18 (dd, 1H,J1=8.8, J2=1.4, C(6)-H), 7.87(dd, 1H, 1=8.8, J2=0.7, C(7)-H), 4.93 (t,2H, J=5.1, NCH2), 3.91 (t, 3H, J=5.1, OCH2), 3.29 (s, 3H, OCH3).

The intermediate 4-(2′-methoxy-ethyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using2-methoxyethylamine. ¹H NMR (CD₃OD): 8.80 (d, 1H, J=2.1, C(2)-H), 8.05(dd, 1H, J1=9.1, J2=2.1, C(6)-H), 7.10 (d, 1H, J=9.1, C(5)-H), 3.69 (t,2H, J=5.2, NHCH2), 3.60 (t, 3H, J=5.2, OCH2), 3.42 (s, 3H, OCH3).

Example 6.13 Preparation of1-(3′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid

1-(3′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-(3′methoxybenzyl)amino-3-nitro-benzoic acid. m/z (ES+): 284 M+H]+. ¹HNMR (CD₃OD): 8.69 (dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.15 (dd, 1H,J1=8.7, J2=1.4, C(6)-H), 7.72 (dd, 1H, J1=8.7, J2=0.7, C(7)-H), 7.26 (t,1H, J=7.9, C(5′)-H), 7.0-6.8 (m, 3H), 5.94 (s, 2H, NCH2), 3.75 (s, 3H,OCH3).

The intermediate 4-(3′methoxybenzyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using3-methoxybenzylamine. ¹H NMR (CD₃OD): 8.82 (d, 1H, J=2.1, C(2)-H), 7.97(dd, 1H, J1=9.1, J2=2.1, C(6)-H), 7.27 (t, 1H, J=8.1, C(5′)-H), 7.0-6.9(m, 3H), 6.84 (dd, 1H, J1=7.5, J2=2.5, C(5)-H), 4.64 (s, 2H, NHCH12),3.78 (s, 3H, OCH3).

Example 6.14 Preparation of1-(4′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid

1-(4′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-(4′methoxybenzyl)amino-3-nitro-benzoic acid. m/z (ES+): 284 [M+H]+. ¹HNMR (CD₃OD): 8.68 (s, 1H, C(4)-H), 8.14 (dd, 1H, J1=8.8, J2=1.4,C(6)-H), 7.72 (d, 1H, J=8.8, C(7)-H), 7.31 (d, 2H, J=8.7, C(2′)-H), 6.90(d, 2H, J=8.7, C(2′)-H), 5.90 (s, 2H, NCH2), 3.76 (s, 3H, OCH3).

The intermediate 4-(4′methoxybenzyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using4-methoxybenzylamine. ¹H NMR (CD₃OD): 8.81 (d, 1H, J=2.0, C(2)-H), 7.98(dd, 1H, J1=9.0, J2=2.0, C(6)-H), 7.31 (d, 2H, J=8.8, C(2′)-H), 7.00 (d,1H, 1=9.0, C(5)-H), 6.91 (d, 2H, J=8.8, C(3′)-H) 4.59 (s, 2H, NHCH2),3.78 (s, 3H, OCH3).

Example 6.15 Preparation of1-[2′-(4″-Methoxy-phenyl)-ethylamino]-1H-benzotriazole-5-carboxylic acid

1-[2′-(4″-Methoxy-phenyl)-ethylamino]-1H-benzotriazole-5-carboxylic acidwas prepared in a similar manner as described in Example 6.1 using4-[2′-(4″-methoxy-phenyl)-ethylamino]-3-nitro-benzoic acid. m/z (ES+):298 [M+H]+. ¹H NMR (CD₃OD): 8.41 (s, 1H, C(4)-H), 7.84 (dd, 1H, J1=8.8,J2=1.3, C(6)-H), 7.29 (d, 1H, J=8.8, C(7)-H), 6.72 (d, 2H, J=8.6,C(2″)-H), 6.50 (d, 2H, J=8.6, C(3″)-H), 4.73 (t, 2H, J=6.8, NCH2), 3.48(s, 3H, OCH3), 5.90 (t, 2H, J=6.8, NCH2CH2).

The intermediate 4-[2′-(4″-methoxy-phenyl)-ethylamino]-3-nitro-benzoicacid was prepared in a similar manner as described in Example 6.1 a.using 2-(4-methoxy-phenyl)-ethylamine. ¹H NMR (CD₃OD): 8.77 (d, 1H,J=2.0, C(2)-H), 8.02 (dd, 1H, J1=9.1, J2=2.0, C(6)-H), 7.20 (d, 2H,J=8.6, C(2″)-H), 7.06 (d, 1H, J=9.1, C(5)-H), 6.87 (d, 2H, J=8.6,C(3′)-H) 3.78 (s, 3H, OCH3), 3.65 (t, 2H, J=7.0, NHCH2), 2.96 (t, 2H,J=7.0, NHCH2CH2).

Example 6.16 Preparation of1-[2′-(3″-Methoxy-phenyl)-ethylamino]-1H-benzotriazole-5-carboxylic acid

1-[2′-(3″-Methoxy-phenyl)-ethylamino]-1H-benzotriazole-5-carboxylic acidwas prepared in a similar manner as described in Example 6.1 using4-[2′-(4″-methoxy-phenyl)-ethylamino]-3-nitro-benzoic acid. m/z (ES+):298 [M+H]+. ¹H NMR (CD₃OD): 8.61 (dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.03(dd, 1H, J1=8.8, J2=1.4, C(6)-H), 7.48 (dd, 1H, J1=8.8, J2=0.7, C(7)-H),7.06 (t, 1H, J=7.9, C(5″)-H), 6.69 (ddd, 1H, J1=8.3, J2=2.5, J2=0.6,C(6″)-H), 6.61 (d, 1H, J=7.5, C(4″)-H), 6.53 (t, 1H, J=2.0, C(2″)-H),4.98 (t, 2H, J=6.8, NCH2), 3.62 (s, 3H, OCH3), 3.27 (t, 2H, J=6.8,NCH2CH2).

The intermediate 4-[2′-(3″-methoxy-phenyl)-ethylamino]-3-nitro-benzoicacid was prepared in a similar manner as described in Example 6.1 a.using 2-(3-methoxy-phenyl)-ethylamine. ¹H NMR (CD₃OD): 8.77 (d, 1H,J=2.1, C(2)-H), 8.02 (dd, 1H, J1=9.1, J2=2.1, C(6)-H), 7.22 (t, 1H,J=8.6, C(5″)-H), 7.06 (d, 1H, J=9.1, C(S)-H), 6.90-6.85 (m, 2H)6.85-6.75 (m, 1H), 3.78 (s, 3H, OCH3), 3.68 (t, 2H, J=7.0, NHCH2), 3.00(t, 2H, J=7.0, NHCH2CH2).

Example 6.17 Preparation of1-(3′,5′-Difluorobenzyl)-1H-benzotriazole-5-carboxylic acid

1-(3′,5′-Difluorobenzyl)-1H-benzotriazole-5-carboxylic acid was preparedin a similar manner as described in Example 6.1 using4-(3′,5′-difluorobenzyl)amino-3-nitro-benzoic acid. m/Z (ES+): 290M+H]+. ¹H NM (CD₃OD): 8.72 (dd, 1H, J1=1.4, J2=0.6, C(4)-H), 8.20 (dd,1H, J1=8.8, J2=1.4, C(6)-H), 7.78 (dd, 1H, J1=8.8, J2=0.6, C(7)-H),7.00-6.90 (m, 3H), 6.00 (s, 2H, NCH2).

The intermediate 4-(3′,5′-difluorobenzyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using3,5-difluoro-benzylamine. ¹H NMR (CD₃OD): 8.34 (d, 1H, J=2.0, C(2)-H),7.99 (dd, 1H, J1=8.6, J2=2.0, C(6)-H), 7.05-6.85 (m, 4H), 4.71 (s, 2H,NHCH2).

Example 6.18 Preparation of1-(2-Ethylsulfanyl-ethyl)-1H-benzotriazole-5-carboxylic acid

1-(2-Ethylsulfanyl-ethyl)-1H-benzotriazole-5-carboxylic acid wasprepared in a similar manner as described in Example 6.1 using4-(2-ethylsulfanyl-ethylamino)-3-nitro-benzoic acid. ¹H NMR (CD₃OD):8.69 (d, 1H, J=0.8, C(4)-H), 8.21 (dd, 1H, J1=8.8, J2=1.4, C(6)-H), 7.89(d, 1H, J=8.8, C(7)-H), 4.95 (t, 2H, J=6.8, NCH2), 3.18 (t, 2H, J=6.8,NCH2CH2), 2.48 (q, 2H, J=7.6, CH2CH3), 1.18 (t, 3H, J=7.4, CH2CH3).

The intermediate 4-(2-ethylsulfanyl-ethylamino)-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using2-ethylsulfanyl-ethylamine. ¹H NMR (CDCl₃): 8.99 (d, 1H, J=1.9, C(2)-H,8.68 (br s, 1H, NH, 8.12 (dd, 1H, J₁=9.0, J₂=1.9, C(6)-H, 6.97 (d, 1H,J=9.1, C(5)-H), 3.61 (q like, 2H, J=6.3, NHCH ² ), 2.91 (t, 2H, J=6.8,NCH₂CH2), 2.63 (q, 2H, J=7.4, CH ² CH₃), 1.32 (t, 3H, J=7.4, CH ³ ).

Example 6.19 Preparation of 1-t-Butyl-1H-benzotriazole-5-carboxylic acid

1-t-Butyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.1 using4-tert-butylamino-3-nitro-benzoic acid. ¹H NMR (CD₃OD): 8.68 (dd, 1H,J1=1.5, J2=0.6, C(4)-H), 8.17 (dd, 1H, J1=8.9, J2=1.5, C(6)-H), 8.07(dd, 1H, J1=8.8, J2=0.6, C(7)-H), 1.90 (s, 9H, CH3).

The intermediate 4-tert-butylamino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using tert-butylamine.¹H NMR (CD₃OD): 9.04 (d, 1H, J=2.1, C(2)-H, 8.25 (dd, 1H, J₁=9.2,J₂=2.1, C(6)-H, 7.54 (d, 1H, J=9.2, C(5)-H), 1.78 (s, 9H, CH ³ ).

Example 6.20 Preparation of1-(3′-Hydroxy-propyl)-1H-benzotriazole-5-carboxylic acid

1-(3′-Hydroxy-propyl)-1H-benzotriazole-5-carboxylic acid was prepared ina similar manner as described in Example 6.1 using4-(3-hydroxy-propylamino)-3-nitro-benzoic acid. ¹H NMR (CD₃OD): 8.69(dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.21 (dd, 1H, J1=8.8, J2=1.4, C(6)-H),7.88 (dd, 1H, J1=8.8, J2=0.7, C(7)-H), 4.87 (t, 2H, J=6.8, NCH2), 3.59(t, 2H, J=6.0, CH2OH), 2.22 (quintet like, 2H, J=6.5, CH2CH2CH2).

The intermediate 4-(3-hydroxy-propylamino)-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using3-hydroxy-propylamine. ¹H NMR (CD₃OD): 8.81 (d, 1H, J=1.9, C(2)-H), 8.05(dd, 1H, J₁=9.1, J₂=1.9, C(6)-H, 7.11 (d, 1H, J=9.1, C(5)-H), 3.73 (t,2H, J=5.9, CH ² OH), 3.55 (t, 2H, J=6.8, NHCH ² ), 1.94 (quintet like,2H, J=6.3, CH ² CH₂OH).

Example 6.21 Preparation of1-(1′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid

1-(1′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid was preparedin a similar manner as described in Example 6.1 using1-(1′,3′-dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid. ¹H NMR(CD₃OD): 8.69 (d, 1H, J=0.8, C(4)-H), 8.20 (dd, 1H, J1=8.8, J2=1.4,C(6)-H), 7.91 (d, 1H, J=8.8, C(7)-H), 5.25-5.15 (m, 1H, NCH), 2.35-2.20(m, 1H), 1.90-1.75 (m, 1H), 1.70 (d, 3H, J=6.4, NCHCH3), 1.30-1.15 (m,1H), 0.95 (d, 3H, J=6.8, CH3), 0.85 (d, 3H, J=6.4, CH3).

The intermediate 1-(1′,3′-dimethyl-butyl)-1H-benzotriazole-5-carboxylicacid was prepared in a similar manner as described in Example 6.1 a.using 1,3-dimethyl-butylamine. ¹H NMR (CD₃OD): 8.69 (d, 1H, J=0.8,C(4)-H, 8.20 (dd, 1H, J₁=8.8, J₂=1.4, C(6)-H, 7.91 (d, 1H, J=8.8,C(7)-H, 5.25-5.15 (m, 1H, NCH, 2.35-2.20 (m, 1H), 1.90-1.75 (m, 1H),1.70 (d, 3H, J=6.4, NCHCH ³ ), 1.30-1.15 (m, 1H), 0.95 (d, 3H, J=6.8, CH³ ), 0.85 (d, 3H, J=6.4, CH ³ ).

Example 6.22 Preparation of1-(3′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid

1-(3′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid was preparedin a similar manner as described in Example 6.1 using1-(3′,3′-dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid. ¹H NMR(CD₃OD): 8.68 (s, 1H, C(4)-H), 8.22 (dd, 1H, J1=8.8, J2=1.4, C(6)-H),7.84 (dd, 1H, J1=8.8, J2=0.6, C(7)-H), 4.85-4.75 (m, 2H, NCH2),1.96-1.90 (m, 2H, NCH2CH2), 1.05 (s, 6H, CH3).

The intermediate 1-(3′,3′-dimethyl-butyl)-1H-benzotriazole-5-carboxylicacid was prepared in a similar manner as described in Example 6.1 a.using 3,3-dimethyl-butylamine. ¹H NMR (CD₃OD): 8.68 (s, 1H, C(4)-H, 8.22(dd, 1H, J₁=8.8, J₂=1.4, C(6)-H), 7.84 (dd, 1H, J₁=8.8, J₂=0.6, C(7)-H),4.85-4.75 (m, 2H, NCH ² ), 1.96-1.90 (m, 2H, NCH₂CH ² ), 1.05 (s, 6H, CH³ ).

Example 6.23 Preparation of 1-Heptyl-1H-benzotriazole-5-carboxylic acid

1-Heptyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.1 using 4-heptylamino-3-nitro-benzoicacid. ¹H NMR (CD₃OD): 8.67 (s, 1H, C(4)-H), 8.20 (dd, 1H, J1=8.7,J2=1.3, C(6)-H), 7.83 (d, 1H, J=8.7, C(7)-H), 4.75 (t, 2H, J=6.8, NCH2),2.05-2.00 (m, 2H, NCH2CH2), 1.5-1.3 (m, 8H), 1.0-0.8 (m, 3H).

The intermediate 4-heptylamino-3-nitro-benzoic acid was prepared in asimilar manner as described in Example 6.1 a. using heptylamine. ¹H NMR(CDCl₃): 8.94 (d, 1H, J=2.0, C(2)-H), 8.42 (t, 1H, J=4.9, NH), 8.07 (dd,1H, J₁=9.1, J₂=2.0, C(6)-H), 6.88 (d, 1H, J=9.1, C(5)-H), 3.36 (q like,2H, J=6.5, NHCH ² ), 1.76 (quintet like, 2H, J=7.3, NCH₂CH ² ), 1.5-1.3(m, 8H), 1.0-0.8 (m, 3H).

Example 6.24 Preparation of1-(2′-Methoxy-1′-methyl-ethyl)-1H-benzotriazole-5-carboxylic acid

1-(2‘-Methoxy-1 ’-methyl-ethyl)-1H-benzotriazole-5-carboxylic acid wasprepared in a similar manner as described in Example 6.1 using4-(2′-methoxy-1′-methyl-ethyl)amino-3-nitro-benzoic acid. ¹H NMR(CD₃OD): 8.68 (s, 1H, C(4)-H), 8.18 (dd, 1H, J1=8.8, J2=1.3, C(6)-H),7.88 (d, 1H, J=8.8, C(7)-H), 5.35-5.25 (m, 1H, NCH), 3.93 (dd, 1H,J1=10.0, J2=8.4, CHCHH), 3.85 (dd, 1H, J1=10.0, J2=4.4, CHCHH), 3.25 (s,3H, OCH3), 1.73 (d, 3H, J=6.8, CH3).

The intermediate 4-(2′-methoxy-1′-methyl-ethyl)amino-3-nitro-benzoicacid was prepared in a similar manner as described in Example 6.1 a.using 2-methoxy-1-methyl-ethylamine. ¹H NMR (CD₃OD): 8.80 (d, 1H, J=2.1,C(2)-H), 8.04 (dd, 1H, J₁=9.1, J₂=2.1, C(6)-H), 7.13 (d, 1H, J=9.1,C(5)-H), 4.08 (sextet like, 1H, J=5.4, NHCH), 3.60-3.50 (m, 2H, CHCH ²), 3.41 (s, 3H, OCH ³ ), 1.33 (d, 3H, J=6.8, CH ³ ).

Example 6.25 Preparation of1-(2′-Hydroxy-1′-hydroxymethyl-ethyl)-1H-benzotriazole-5-carboxylic acid

1-(2′-Hydroxy-1′-hydroxymethyl-ethyl)-1H-benzotriazole-5-carboxylic acidwas prepared in a similar manner as described in Example 6.1 using4-(2′-hydroxy-1′-hydroxymethyl-ethyl)amino-3-nitro-benzoic acid. ¹H NMR(CD₃OD): 8.68 (s, 1H, C(4)-H), 8.19 (dd, 1H, J1=8.8, J2=1.4, C(6)-H),7.88 (d, 1H, J=8.8, C(7)-H), 5.10-5.00 (m, 1H, NCH), 4.25-4.10 (m, 4H,CH2OH).

The intermediate4-(2′-hydroxy-1′-hydroxymethyl-ethyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using2-hydroxy-1-hydroxymethyl-ethylamine. m/z (ES⁺): 257 [M+H]⁺. ¹H NMR(CD₃OD): 8.81 (d, 1H, J=2.1, C(2)-H), 8.03 (dd, 1H, J₁=9.2, J₂=2.1,C(6)-H), 7.18 (d, 1H, J=9.2, C(5)-H), 3.90 (quintet like, 1H, J=5.0,NHCH), 3.85-3.70 (r, 4H, CH ² OH).

Example 6.26 Preparation of 1-Ethyl-1H-benzotriazole-5-carboxylic acid

1-Ethyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.1 using 4-ethylamino-3-nitro-benzoicacid. ¹HNMR (CD₃OD): 8.69 (d, 1H, J=0.7, C(4)-H), 8.21 (dd, 1H, J1=8.8,J2=1.3, C(6)-H), 7.86 (dd, 1H, J1=8.8, J2=0.7, C(7)-H), 4.80 (q, 2H,J=7.4, NCH2), 1.63 (t, 3H, J=7.4, CH3).

The intermediate 4-ethylamino-3-nitro-benzoic acid was prepared in asimilar manner as described in Example 6.1 a. using2-methoxy-1-methyl-ethylamine. ¹H NMR (CD₃OD): 8.80 (d, 1H, J=2.1,C(2)-H, 78.05 (dd, 1H, J₁=9.1, J₂=2.1, C(6)-H), 7.07 (d, 1H, J=9.1,C(5)-H, 3.48 (q, 2H, J=7.2, NHCH ² ), 1.35 (t, 3H, J=7.2, CH ³ ).

Example 6.27 Preparation of 1-Pentyl-1H-benzotriazole-5-carboxylic acid

1-Pentyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.1 using 4-pentylamino-3-nitro-benzoicacid. ¹H NMR (CD₃OD): 8.69 (d, 1H, J=0.8, C(4)-1H), 8.21 (dd, 1H,J1=8.8, J2=1.4, C(6)-H), 7.86 (dd, 1H, J1=8.8, J2=0.6, C(7)-H), 4.76 (q,2H, J=7.2, NCH2), 2.10-1.95 (m, 2H, NCH2CH2), 1.45-1.25 (m, 4H), 0.90(t, 3H, J=7.2, CH3).

The intermediate 4-pentylamino-3-nitro-benzoic acid was prepared in asimilar manner as described in Example 6.1 a. using pentylamine. ¹H NMR(CD₃OD): 8.66 (d, 1H, J=2.1, C(2)-H), 7.91 (dd, 1H, J₁=9.1, J₂=2.1,C(6)-H), 6.93 (d, 1H, J=9.1, C(5)-H), 3.29 (t, 2H, J=7.2, NHCH ² ), 1.62(quintet like, 2H, J=7.0, NCH₂CH ² ), 1.35-1.25 (m, 4H), 0.83 (t, 3H,J=7.1, CH ³ ).

Example 6.28 Preparation of1-(2′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid

1-(2′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid wasprepared in a similar manner as described in Example 6.1 using4-(2′,2′-dimethyl-propyl)amino-3-nitro-benzoic acid. ¹H NMR (CD₃OD):8.69 (dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.20 (dd, 1H, J1=8.8, J2=1.4,C(6)-H), 7.86 (dd, 1H, J1=8.8, J2=0.7, C(7)-H), 4.56 (s, 2H, NCH2), 1.05(s, 9H, CH3).

The intermediate 4-(2′,2′-dimethyl-propyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using2,2-dimethyl-propylamine. ¹H NMR (CD₃OD): 8.81 (d, 1H, J=2.1, C(2)-H),8.04 (dd, 1H, J₁=9.1, J₂=2.1, C(6)-H), 7.13 (d, 1H, J=9.1, C(5)-H), 3.25(s, 2H, NHCH ² ), 1.08 (s, 9H, CH ³ ).

Example 6.29 Preparation of1-(2′-Ethoxy-ethyl)-benzotriazole-5-carboxylic acid

1-(2′-Ethoxy-ethyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using42′-ethoxy-ethyl)amino-3-nitro-benzoic acid. ¹H NMR (CD₃OD): 8.68 (d,1H, J=0.8, C(4)-H), 8.18 (dd, 1H, J1=8.8, J2=1.3, C(6)-H), 7.88 (dd, 1H,J1=8.8, J2=0.6, C(7)-H), 4:92 (t, 2H, J=5.2, NCH2), 3.95 (t, 2H, J=5.0,NCH2CH2), 3.44 (q, 2H, J=7.0, CH2CH3), 1.04 (t, 3H, J=7.0, CH3).

The intermediate 4-(2′-ethoxy-ethyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using2-ethoxy-ethylamine. ¹H NMR (CD₃OD): 8.80 (d, 1H, J=2.0, C(2)-H), 8.05(dd, 1H, J₁=9.1, J₂=2.0, C(6)-H), 7.10 (d, 1H, J=9.1, C(5)-H), 3.74 (t,2H J=7.0, NHCH₂CH ² ), 3.65-3.55 (m, 4H, NHCH ² & CH ² CH₃), 1.22 (t,3H, J=7.0, CH ³ ).

Example 6.30 Preparation of1-(1′,2′-Dimethyl-propyl)-11H-benzotriazole-5-carboxylic acid

1-(1′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid wasprepared in a similar manner as described in Example 6.1 using4-(1′,2′-dimethyl-propyl)amino-3-nitro-benzoic acid. ¹H NMR (CD₃OD):8.69 (dd, 1H, J1=1.4, J2=0.5, C(4)-H), 8.19 (dd, 1H, J1=8.8, J2=1.4,C(6)-H), 7.88 (dd, 1H, J1=8.8, J2=0.5, C(7)-H), 4.85-4.75 (m, 1H, NCH),2.45-2.35 (m, 1H, J=5.0, CH(CH3)2), 1.74 (d, 3H, J=6.4, NCHCH3), 1.09(d, 3H, J=6.8, CH3), 0.75 (d, 3H, J=6.8, CH3).

The intermediate 4-(1′,2′-dimethyl-propyl)amino-3-nitro-benzoic acid wasprepared in a similar manner as described in Example 6.1 a. using1,2-dimethyl-propylamine. ¹H NMR (CD₃OD): 8.81 (d, 1H, J=2.1, C(2)-H),8.04 (dd, 1H, J₁=9.1, J₂=2.1, C(6)-H), 7.11 (d, 1H, J=9.1, C(5)-H), 3.78(quintet like, 1H, NHCH, 2.00-1.90 (m. 1H, CH(CH₃)₂), 1.27 (d, 3H,J=6.5, NCHCH ₃), 1.06 (d, 3H, J=6.9, CH ₃), 1.01 (d, 3H, J=6.8, CH ³ ).

Example 6.31 Preparation of 1-Benzhydryl-1H-benzotriazole-5-carboxylicacid

1-Benzhydryl-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.1 using4-benzhydrylamino-3-nitro-benzoic acid. ¹H NMR (CD₃OD): 8.72 (s, 1H,C(4)-H), 8.07 (d, 1H, J=8.8, C(6)-H), 7.48 (d, 1H, J=8.8, C(7)-H),7.40-7.20 (m, 10H), 4.96 (s, 1H, NCH).

The intermediate 4-benzhydrylamino-3-nitro-benzoic acid was prepared ina similar manner as described in Example 6.1 a. using benzhydrylamine.¹H NMR (CD₃OD): 8.69 (d, 1H, J=2.0, C(2)-H), 7.79 (dd, 1H, J₁=9.1,J₂=2.0, C(6)-H), 7.30-7.15 (m, 10H), 6.77 (d, 1H, J=9.1, C(5)-H), 5.88(br s, 1H, NHCH).

Example 6.32 Preparation of 1-Allyl-1H-benzotriazole-5-carboxylic acid

Benzotriazole-5-carboxylic acid (0.163 g, 1.0 mmol), allyl bromide (0.18g, 1.5 mmol) and potassium carbonate (0.304 g, 2.2 mmol) were stirredfor 18 hours at 60° C. in DMA (3 mL). The resulting solution was dilutedwith water and acetonitrile until all solid was dissolved, and purifiedby preparative HPLC to give 1-(allyl)-1H-benzotriazole-5-carboxylic acidm/z (ES+): 204 [+H]+. ¹H NMR (CD₃OD): 8.73 (s, 1H, C(4)-H), 8.19 (dd,1H, J1=8.8, J2=1.6, C(6)-H), 7.85 (d, 1H, J=8.4, C(7)-H), 6.1-6.0 (m,1H, CH═CH2), 5.50-5.40 (m, 1H, CH═CHH trans to H), 5.35-5.30 (m, 1H,CH═CHH cis to H), 4.90-4.85 (m, 2H, NCH2).

Example 6.33 Preparation of 1-Butyl-1H-benzotriazole-5-carboxylic acid

1-Butyl-1H-benzotriazole-5-carboxylic acid was prepared in a similarmanner as described in Example 6.32 using butyl bromide. m/z (ES+): 220M+H]+. ¹H NMR (CD₃OD): 8.68 (dd, 1H, J1=1.4, J2=0.6, C(4)-H), 8.20 (dd,1H, J1=8.8, J2=1.4, C(6)-H), 7.86 (dd, 1H, J1=8.4, J2=0.6, C(7)-H), 4.76(t, 2H, J=7.0, NCH2), 2.05-1.95 (m, 2H, NCH2CH2), 1.3-40-1.25 (m, 2H,CH2CH3), 0.97 (t, 3H, J=7.4, CH3).

Example 6.34 Preparation of1-(Cyclopropylmethyl)-1H-benzotriazole-5-carboxylic acid

1-(Cyclopropylmethyl)-1H-benzotriazole-5-carboxylic acid was prepared ina similar manner as described in Example 6.32 using cyclopropylmethylbromide. m/z (ES+): 218 [M+H]+. ¹H NMR (CD₃OD): 8.46 (s, 1H, C(4)-H),8.03 (dd, 1H, J1=8.9, J2=0.9, C(6)-H), 7.79 (d, 1H, J=8.9, C(7)-H), 4.60(d, 2H, J=7.6, NCH2), 1.55-1.50 (m, 1H, NCH2CH), 0.70-0.60 (m, 2H),0.60-0.50 (m, 2H).

Example 6.35 Preparation of 1-(But-2-ynyl)-1H-benzotriazole-5-carboxylicacid

1-(But-2-ynyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.32 using 1-bromo-but-2-yne. m/z(ES+): 216 [M+H]+. ¹H NMR (CD₃OD): 8.79 (s, 1H, C(4)-H), 8.21 (d, 1H,J=9.4, C(6)-H), 7.91 (d, 1H, J=8.8, C(7)-H), 4.97 (s, 2H, NCH2), 1.90(s, 3H, CH3).

Example 6.36 Preparation of1-(4′-Methyl-pentyl)-1H-benzotriazole-5-carboxylic acid

1-(4′-Methyl-pentyl)-1H-benzotriazole-5-carboxylic acid was prepared ina similar manner as described in Example 6.32 using1-bromo-4-methyl-pentane. m/z (ES+): 248 [M+H]+. ¹H NMR (CD₃OD): 8.69(dd, 1H, J1=1.4, J2=0.7, C(4)-H), 8.21 (dd, 1H, J1=8.8, J2=1.4, C(6)-H),7.86 (dd, 1H, J1=8.8, J2=0.7, C(7)-H), 4.75 (t, 2H, J=7.0, NCH2),2.10-2.00 (m, 2H, NCH2CH2), 1.65-1.55 (m, 1H, CH(CH3)2), 1.30-1.15 (m,2H, CH2CH), 0.89 (d, 6H, J=6.8, CH3).

Example 6.37 Preparation of1-(3′-Methyl-butyl)-1H-benzotriazole-5-carboxylic acid

1-(3′-Methyl-butyl)-1H-benzotriazole-5-carboxylic acid was prepared in asimilar manner as described in Example 6.32 using1-bromo-3-methyl-butane. ¹H NMR (CD₃OD): 8.69 (d, 1H, 3=0.8, C(4)-H),8.21 (dd, 1H, J1=8.8, J2=1.4, C(6)-H), 7.86 (dd, 1H, J1=8.8, J2=0.7,C(7)-H), 4.79 (t 2H, J=7.4, NCH2), 1.92 (q like, 2H, J=7.2, NCH2CH2),1.60-1.50 (m, 1H, CH(CH3)2), 1.00 (d, 6H, J=6.4, CH3).

Example 7

In Vivo Animal Model

The utility of the compound of the present invention as a medical agentin the prophylaxis and treatment of a high totalcholesterol/HDL-cholesterol ratio and conditions relating thereto isdemonstrated by the activity of the compound in lowering the ratio oftotal cholesterol to HDL-cholesterol, in elevating HDL-cholesterol, orin protection from atherosclerosis in an in viva pig model. Pigs areused as an animal model because they reflect human physiology,especially lipid metabolism, more closely than most other animal models.An illustrative in vivo pig model not intended to be limiting ispresented here.

Yorkshire albino pigs (body weight 25.5±4 kg) are fed a saturated fattyacid rich and cholesterol rich (SFA-CHO) diet during 50 days (1 kg chow35 kg⁻¹ pig weight), composed of standard chow supplemented with 2%cholesterol and 20% beef tallow [Royo T et al., European Journal ofClinical Investigation (2000) 30:843-52; which disclosure is herebyincorporated by reference in its entirety]. Saturated to unsaturatedfatty acid ratio is modified from 0.6 in normal pig chow to 1.12 in theSFA-CHO diet. Animals are divided into two groups, one group (n=8) fedwith the SFA-CHO diet and treated with placebo and one group (n=8) fedwith the SFA-CHO diet and treated with the compound (3.0 mg kg⁻¹).Control animals are fed a standard chow for a period of 50 days. Bloodsamples are collected at baseline (2 days after the reception of theanimals), and 50 days after the initiation of the diet. Blood lipids areanalyzed. The animals are sacrificed and necropsied.

Alternatively, the foregoing analysis comprises a plurality of groupseach treated with a different dose of the compound. Preferred said dosesare selected from the group consisting of: 0.1 mg kg⁻¹, 0.3 mg kg⁻¹, 1.0mg kg⁻¹, 3.0 mg kg⁻¹, 10 mg kg⁻¹, 30 mg kg⁻¹ and 100 mg kg⁻¹.Alternatively, the foregoing analysis is carried out at a plurality oftimepoints. Preferred said timepoints are selected from the groupconsisting of 10 weeks, 20 weeks, 30 weeks, 40 weeks, and 50 weeks.

HDL-Cholesterol

Blood is collected in trisodium citrate (3.8%, 1:10). Plasma is obtainedafter centrifugation (1200 g 15 min) and immediately processed. Totalcholesterol, HDL-cholesterol, and LDL-cholesterol are measured using theautomatic analyzer Kodak Ektachem DT System (Eastman Kodak Company,Rochester, N.Y., USA). Samples with value parameters above the range arediluted with the solution supplied by the manufacturer and thenre-analyzed. The total cholesterol/HDL-cholesterol ratio is determined.Comparison is made of the level of HDL-cholesterol between groups.Comparison is made of the total cholesterol/HDL-cholesterol ratiobetween groups.

Elevation of HDL-cholesterol or reduction of the totalcholesterol/HDL-cholesterol ratio on administration of the compound istaken as indicative of the compound having the aforesaid utility.

Atherosclerosis

The thoracic and abdominal aortas are removed intact, openedlongitudinally along the ventral surface, and fixed in neutral-bufferedformalin after excision of samples from standard sites in the thoracicand abdominal aorta for histological examination and lipid compositionand synthesis studies. After fixation, the whole aortas are stained withSudan IV and pinned out flat, and digital images are obtained with a TVcamera connected to a computerized image analysis system (Image ProPlus; Media Cybernetics, Silver Spring, Md.) to determine the percentageof aortic surface involved with atherosclerotic lesions [Gerrity R G etal, Diabetes (2001) 50:1654-65; Cornhill J F et al, Arteriosclerosis,Thrombosis, and Vascular Biology (1985) 5:415-26; which disclosures arehereby incorporated by reference in their entirety]. Comparison is madebetween groups of the percentage of aortic surface involved withatherosclerotic lesions.

Reduction of the percentage of aortic surface involved withatherosclerotic lesions on administration of the compound is taken asindicative of the compound having the aforesaid utility.

Example 8

Receptor Binding Assay

In addition to the methods described herein, another means forevaluating a test compound is by determining binding affinities to theRUP38 receptor. This type of assay generally requires a radiolabelledligand to the RUP38 receptor. Absent the use of known ligands for theRUP38 receptor and radiolabels thereof, compounds of Formula (I) can belabelled with a radioisotope and used in an assay for evaluating theaffinity of a test compound to the RUP38 receptor.

A radiolabelled RUP38 compound of Formula (I) can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radiolabelledcompound of Formula (I)” to the RUP38 receptor. Accordingly, the abilityto compete with the “radio-labelled compound of Formula (a)” orRadiolabelled RUP38 Ligand for the binding to the RUP38 receptordirectly correlates to its binding affinity of the test compound to theRUP38 receptor.

Assay Protocol for Determining Receptor Binding for RUP38:

A. RUP38 Receptor Preparation

293 cells (human kidney, ATCC), transiently transfected with 10 ug humanRUP38 receptor and 60 ul Lipofectamine (per 15-cm dish), are grown inthe dish for 24 hours (75% confluency) with a media change and removedwith 10 ml/dish of Hepes-EDTA buffer (20 mM Hepes+10 mM EDTA, pH 7.4).The cells are centrifuged in a Beckman Coulter centrifuge for 20minutes, 17,000 rpm (JA-25.50 rotor). Subsequently; the pellet isresuspended in 20 mM Hepes+1 mM EDTA, pH 7.4 and homogenized with a50-ml Dounce homogenizer and again centrifuged. After removing thesupernatant, the pellets are stored at −80° C., until used in bindingassay. When used in the assay, membranes are thawed on ice for 20minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCl₂,100 mM NaCl, pH 7.4) added. The membranes are vortexed to resuspend thecrude membrane pellet and homogenized with a Brinkmann PT-3100 Polytronhomogenizer for 15 seconds at setting 6. The concentration of membraneprotein is determined using the BRL Bradford protein assay.

B. Biding Assay

For total binding, a total volume of 50 ul of appropriately dilutedmembranes (diluted in assay buffer containing 50 mM Tris HCl (pH 7.4),10 mM MgCl₂, and 1 mM EDTA; 5-50 ug protein) is added to 96-wellpolyproylene microtiter plates followed by addition of 100 ul of assaybuffer and 50 ul of Radiolabelled RUP38 Ligand. For nonspecific binding,50 ul of assay buffer is added instead of 100 ul and an additional 50 ulof 10 uM cold RUP38 is added before 50 ul of Radiolabelled RUP38 Ligandis added. Plates are then incubated at room temperature for 60-120minutes. The binding reaction is terminated by filtering assay platesthrough a Microplate Devices GF/C Unifilter filtration plate with aBrandell 96-well plate harvestor followed by washing with cold 50 mMTris HCl, pH 7.4 containing 0.9% NaCl. Then, the bottom of thefiltration plate are sealed, 50 ul of Optiphase Supermix is added toeach well, the top of the plates are sealed, and plates are counted in aTrilux MicroBeta scintillation counter. For compound competitionstudies, instead of adding 100 ul of assay buffer, 100 ul ofappropriately diluted test compound is added to appropriate wellsfollowed by addition of 50 ul of Radiolabelled RUP38 Ligand.

C. Calculations

The test compounds are initially assayed at 1 and 0.1 μM and then at arange of concentrations chosen such that the middle dose would causeabout 50% inhibition of a Radio-RUP38 Ligand binding (i.e., IC₅₀).Specific binding in the absence of test compound (B_(O)) is thedifference of total binding (B_(T)) minus non-specific binding (NSB) andsimilarly specific binding (in the presence of test compound) (B) is thedifference of displacement binding (B_(D)) minus non-specific binding(NSB). IC₅₀ is determined from an inhibition response curve, logit-logplot of % B/B_(O) vs concentration of test compound.

K_(i) is calculated by the Cheng and Prustoff transformation:K_(i)=IC₅₀/(1+[L]/K_(D))

where [L] is the concentration of a Radio-RUP38 Ligand used in the assayand K_(D) is the dissociation constant of a Radio-RUP38 Liganddetermined independently under the same binding conditions.

Throughout this application, various publications, patents and publishedpatent applications are cited. The disclosures of these publications,patents and published patent applications referenced in this applicationare hereby incorporated by reference in their entirety into the presentdisclosure. Modifications and extension of the disclosed inventions thatare within the purview of the skilled artisan are encompassed within theabove disclosure and the claims that follow.

Although a variety of expression vectors are available to those in theart, for purposes of utilization for both the endogenous andnon-endogenous human GPCRs, it is most preferred that the vectorutilized be pCMV. This vector was deposited with the American TypeCulture Collection (ATCC) on Oct. 13, 1998 (10801 University Blvd.,Manassas, Va. 20110-2209 USA) under the provisions of the BudapestTreaty for the International Recognition of the Deposit ofMicroorganisms for the Purpose of Patent Procedure. The DNA was testedby the ATCC and determined to be viable. The ATCC has assigned thefollowing deposit number to pCMV: ATCC #203351.

1. A compound of Formula (I):

wherein: R₁ is C₁₋₈ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, whereinthe C₁₋₈ alkyl, C₃₋₆ cycloalkyl and C₁₋₆ haloalkyl groups are optionallysubstituted with 1, 2, 3 or 4 substituents selected from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino,aryl, substituted aryl, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₄ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl, heterocyclyl,hydroxyl, nitro and thiol; R₂, R₃ and R₄ are each independently selectedfrom the group consisting of H, C₁₋₆acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl,C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro and thiol; and R₅is H or C₁₋₆ alkyl; or a pharmaceutically acceptable salt solvate orhydrate thereof; provided that: a) when R₅ is ethyl, and R₂, R₃ and R₄are H then R₁ is not methyl or triphenylmethyl; b) when R₅ is n-pentyl,and R₂, R₃ and R₄ are H then R₁ is not n-butyl; c) when R₅ is methyl,and R₂, R₃ and R₄ are H then R₁ is not pyrrolidin-1-ylmethyl,3-tert-butyl-2-hydroxy-5-methyl-benzyl, methyl, or dimethylaminomethyl;d) when R₅ is methyl, R₂ is carbomethoxy and R₃ and R₄ are both H thenR₁ is not methyl; e) when R₂, R₃, R₄ and R₅ are all H then R₁ is not2-amino-2-carboxy-ethyl, pyrrolidin-1-ylmethyl, isopropyl, methyl,benzyl, n-butyl, or carboxymethyl; and f) when R₂, R₄, and R₅ are all Hand R₃ is methoxy then R₁ is not methyl.
 2. A compound according toclaim 1 wherein: R₁ is C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, wherein eachC₃₋₆ cycloalkyl and C₁₋₆ haloalkyl group is optionally substituted with1, 2, 3, or 4 substituents selected form the group consisting of C₁₋₆acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₁₋₆dialkylamino, carbo C₁₋₆ alkoxy, carboxy, cyano, C₃₋₆ cycloalkyl, C₁₋₆dialkylcarboxamido, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,nitro and thiol; R₂, R₃ and R₄ are each independently selected from thegroup consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₄haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro and thiol; and R₅is H or C₁₋₆ alkyl; or a pharmaceutically acceptable salt, solvate orhydrate thereof.
 3. The compound according to claim 1 wherein R₅ is C₁₋₆alkyl.
 4. The compound according to claim 1 wherein R₅ is H.
 5. Thecompound according to claim 1 wherein R₂, R₃ and R₄ are eachindependently H or halogen.
 6. The compound according to claim 1 whereinR₂, R₃ and R₄ are each independently H or F.
 7. The compound accordingto claim 1 wherein R₁ is C₁₋₈ alkyl optionally substituted withsubstituents selected from the group consisting of C₂₋₆ alkenyl, C₁₋₆alkoxy, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, aryl, substituted aryl, C₃₋₆ cycloalkyl, halogen, C₁₋₆haloalkoxy, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heteroaryl, heterocyclyl, and hydroxyl.
 8. The compoundaccording to claim 1 wherein R₁ is selected from the group consisting of2-butyl, 3-pentyl, 1-propyl, t-butyl, 1-butyl, 4-Methyl-pentyl,3-methyl-butyl, 1,3-dimethyl-butyl, 3,3-dimethyl-butyl, 1-heptyl, ethyl,2,2-dimethyl-propyl, and 1-pentyl.
 9. The compound according to claim 1wherein R₁ is selected from the group consisting of 3-methoxy-benzyl,4-methoxy-benzyl, 4-methoxy-phenyl ethyl, 3-methoxy-phenyl ethyl,3,5-difluorobenzyl, and benzhydryl.
 10. The compound according to claim1 wherein R₁ is selected from the group consisting of3-isopropoxypropyl, tetrahydro-furan-2-ylmethyl, 2-methoxy-ethyl,2-ethylsulfanyl-ethyl, 3-hydroxy-propyl, allyl, cyclopropylmethyl,but-2-ynyl, 2-methoxy-1-methyl-ethyl, 2-hydroxy-1-hydroxymethyl-ethyl,2-ethoxy-ethyl, and 1,2-dimethyl-propyl.
 11. The compound according toclaim 1 wherein R₁ is selected from the group consisting of cyclopentyl,cyclohexyl, cyclopropyl, and cyclobutyl.
 12. The compound according toclaim 1 selected from the group consisting of:1-Cyclopentyl-1H-benzotriazole-5-carboxylic acid;1-(2′-Butyl)-1H-benzotriazole-5-carboxylic acid;1-(3′-Pentyl)-1H-benzotriazole-5-carboxylic acid;1-Cyclohexyl-1H-benzotriazole-5-carboxylic acid1-Propyl-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-1H-benzotriazole-5-carboxylic acid;1-(3′-Isopropoxy-propyl)-1H-benzotriazole-5-carboxylic acid;1-(Tetrahydro-furan-2′-ylmethyl)-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-1H-benzotriazole-5-carboxylic acid;1-(2-Methoxy-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(3′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid;1-(4′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid;1-[2′-(4″-Methoxy-phenyl)-ethyl]-1H-benzotriazole-5-carboxylic acid;1-[2′-(3″-Methoxy-phenyl)-ethyl]-1H-benzotriazole-5-carboxylic acid;1-(3′,5′-Difluorobenzyl)-1H-benzotriazole-5-carboxylic acid;1-(2-Ethylsulfanyl-ethyl)-1H-benzotriazole-5-carboxylic acid;1-t-Butyl-1H-benzotriazole-5-carboxylic acid;1-(3′-Hydroxy-propyl)-1H-benzotriazole-5-carboxylic acid;1-(1′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid;1-(3′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid;1-Heptyl-1H-benzotriazole-5-carboxylic acid;1-(2′-Methoxy-1′-methyl-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Hydroxy-1′-hydroxymethyl-ethyl)-1H-benzotriazole-5-carboxylicacid; 1-Ethyl-1H-benzotriazole-5-carboxylic acid;1-Pentyl-1H-benzotriazole-5-carboxylic acid;1-(2′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Ethoxy-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(1′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid;1-Benzhydryl-1H-benzotriazole-5-carboxylic acid;1-Allyl-1H-benzotriazole-5-carboxylic acid;1-Butyl-1H-benzotriazole-5-carboxylic acid;1-(Cyclopropylmethyl)-1H-benzotriazole-5-carboxylic acid;1-(But-2-ynyl)-1H-benzotriazole-5-carboxylic acid;1-(4′-Methyl-pentyl)-1H-benzotriazole-5-carboxylic acid; and1-(3′-Methyl-butyl)-1H-benzotriazole-5-carboxylic acid; or apharmaceutically acceptable salt, solvate or hydrate thereof.
 13. Apharmaceutical composition comprising a compound according to Formula(I):

wherein: R₁ is H, C₁₋₈ alkyl, C₃₋₆ cycloalkyl or C₁₋₆ haloalkyl, whereineach C₁₋₆ alkyl, C₃₋₆ cycloalkyl and C₁₋₆ haloalkyl group is optionallysubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino,C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy, cyano, C₃₋₄ cycloalkyl,C₁₋₆ dialkylcarboxamido, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,nitro and thiol; R₂, R₃ and R₄ are each independently selected from thegroup consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamido, C₂₋₆ alkynyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, carbo C₁₋₆ alkoxy, carboxy,cyano, C₃₋₆ cycloalkyl, C₁₋₆ dialkylcarboxamido, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, nitro and thiol; and R₅is H or C₁₋₆ alkyl; or a pharmaceutically acceptable salt, solvate orhydrate thereof, in combination with a pharmaceutically acceptablecarrier.
 14. A pharmaceutical composition according to claim 13 furthercomprising an agent selected from the group consisting of α-glucosidaseinhibitor, aldose reductase inhibitor, biguanide, HMG-CoA reductaseinhibitor, squalene synthesis inhibitor, fibrate, LDL catabolismenhancer, angiotensin converting enzyme inhibitor, insulin secretionenhancer and thiazolidinedione.
 15. (canceled)
 16. (canceled) 17.(canceled)
 18. (canceled)
 19. (canceled)
 20. A method of treatment of ametabolic-related disorder comprising administering to an individual inneed of such treatment a therapeutically effective amount of apharmaceutical composition according to claim
 13. 21. A method accordingto claim 20 wherein said metabolic-related disorder is selected from thegroup consisting of dyslipidemia, atherosclerosis, coronary heartdisease, insulin resistance and type 2 diabetes.
 22. (canceled) 23.(canceled)
 24. (canceled)
 25. (canceled)
 26. A method of treatment of ametabolic-related disorder comprising administering to an individual inneed of such treatment a therapeutically effective amount of a compoundaccording to claim
 1. 27. A method according to claim 26 wherein saidmetabolic-related disorder is selected from the group consisting ofdyslipidemia, atherosclerosis, coronary heart disease, insulinresistance and type 2 diabetes.
 28. The pharmaceutical compositionaccording to claim 13 wherein said compound is selected from the groupconsisting of: 1-Isopropyl-1H-benzotriazole-5-carboxylic acid;1-Cyclopentyl-1H-benzotriazole-5-carboxylic acid;1-(2′-Butyl)-1H-benzotriazole-5-carboxylic acid;1-(3′-Pentyl)-1H-benzotriazole-5-carboxylic acid;1-Cyclohexyl-1H-benzotriazole-5-carboxylic acid;1-Benzyl-1H-benzotriazole-5-carboxylic acid;1-Propyl-1H-benzotriazole-5-carboxylic acid;1-Cyclopropyl-1H-benzotriazole-5-carboxylic acid;1-(3′-Isopropoxy-propyl)-1H-benzotriazole-5-carboxylic acid;1-(Tetrahydro-furan-2′-ylmethyl)-1H-benzotriazole-5-carboxylic acid;1-Cyclobutyl-1H-benzotriazole-5-carboxylic acid;1-(2-Methoxy-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(3′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid;1-(4′Methoxybenzyl)-1H-benzotriazole-5-carboxylic acid;1-[2′-(4″-Methoxy-phenyl)-ethyl]-1H-benzotriazole-5-carboxylic acid;1-[2′-(3″-Methoxy-phenyl)-ethyl]-1H-benzotriazole-5-carboxylic acid;1-(3′,5′-Difluorobenzyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Ethylsulfanyl-ethyl)-1H-benzotriazole-5-carboxylic acid;1-t-Butyl-1H-benzotriazole-5-carboxylic acid;1-(3′-Hydroxy-propyl)-1H-benzotriazole-5-carboxylic acid;1-(1′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid;1-(3′,3′-Dimethyl-butyl)-1H-benzotriazole-5-carboxylic acid;1-Heptyl-1H-benzotriazole-5-carboxylic acid;1-(2′-Methoxy-1′-methyl-ethyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Hydroxy-1′-hydroxymethyl-ethyl)-1H-benzotriazole-5-carboxylicacid; 1-Ethyl-1H-benzotriazole-5-carboxylic acid;1-Pentyl-1H-benzotriazole-5-carboxylic acid;1-(2′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid;1-(2′-Ethoxy-ethyl)-1H-benzotriazole-5-carboxylic acid;1-1′,2′-Dimethyl-propyl)-1H-benzotriazole-5-carboxylic acid;1-Benzhydryl-1H-benzotriazole-5-carboxylic acid;1-Allyl-1H-benzotriazole-5-carboxylic acid;1-Butyl-1H-benzotriazole-5-carboxylic acid;1-(Cyclopropylmethyl)-1H-benzotriazole-5-carboxylic acid;1-(But-2-ynyl)-1H-benzotriazole-5-carboxylic acid;1-(4′-Methyl-pentyl)-1H-benzotriazole-5-carboxylic acid; and1-(3′-Methyl-butyl)-1H-benzotriazole-5-carboxylic acid; or apharmaceutically acceptable salt, solvate or hydrate thereof.